{"gene":"IGF2","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1978,"finding":"IGF-II (IGF2) was identified as a 67-amino acid single-chain polypeptide (sharing sequence homology with insulin and IGF-I) that accounts for the majority of insulin-like activity remaining in serum after insulin depletion, establishing its primary structure.","method":"Protein purification and primary structure determination","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — original primary structure determination, foundational and replicated","pmids":["658418"],"is_preprint":false},{"year":1984,"finding":"IGF2 is encoded as a 180-amino acid preproprotein (preproIGF-II) containing a C-terminal E-peptide propeptide of 89 amino acids; the gene organization is related to the insulin gene family.","method":"cDNA cloning and sequencing of human IGF2 from adult liver mRNA","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cDNA cloning with direct sequence determination, replicated","pmids":["6382021","6382022"],"is_preprint":false},{"year":1987,"finding":"Human IGF2 is transcribed from at least two promoters with developmentally regulated usage; fetal tissues predominantly use a distinct promoter compared to adult liver, and steady-state IGF2 transcript levels are dramatically reduced in adult compared to fetal organs, indicating a second level of transcriptional control independent of promoter usage.","method":"Northern blot analysis and transcript characterization in fetal and adult human tissues","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 — multiple tissue types examined, developmental regulation documented","pmids":["3503697"],"is_preprint":false},{"year":1993,"finding":"IGF2 is monoallelically expressed (from the paternal allele) in normal human tissues; 69% of Wilms' tumors show biallelic (loss of imprinting) expression of IGF2, establishing loss of imprinting as an epigenetic mutational mechanism in cancer.","method":"Allele-specific RT-PCR using exonic polymorphisms in human tumor and normal tissues","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — allele-specific expression assay in large tumor cohort, highly replicated across labs","pmids":["8385745"],"is_preprint":false},{"year":1994,"finding":"Excess IGF-II acts locally to increase cell number (DNA content) at sites of transgene expression (skin, alimentary canal, uterus) and has systemic effects on adult body weight, demonstrating distinct local and systemic growth-promoting actions of IGF-II in vivo.","method":"Keratin promoter-driven Igf2 transgenic mice; tissue DNA content and organ weight measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple transgenic lines, in vivo functional phenotype","pmids":["7524092"],"is_preprint":false},{"year":1995,"finding":"IGF2 and H19 share common endoderm-specific enhancers located 3' of H19; paternal inheritance of an enhancer deletion abolishes Igf2 expression in endodermal tissues, and mice inheriting the deletion paternally are ~80% of normal size, demonstrating that IGF-II acts systemically to affect prenatal growth.","method":"Targeted deletion of enhancers by homologous recombination; allele-specific expression analysis; growth measurement","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — precise genetic deletion in ES cells, in vivo phenotype in multiple tissues, replicated","pmids":["7544754"],"is_preprint":false},{"year":1995,"finding":"The major 6.0-kb IGF2 mRNA is stored untranslated in a 100S ribonucleoprotein particle in quiescent cells and is selectively mobilized and translated in exponentially growing cells; translational activation is blocked by rapamycin and mimicked by anisomycin, implicating the p70S6K/85S6K kinase signaling pathway in post-transcriptional regulation of IGF2.","method":"Sucrose gradient sedimentation, rapamycin/anisomycin pharmacological inhibition, polysome profiling in dispersed cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, pharmacological dissection of signaling pathway","pmids":["7566093"],"is_preprint":false},{"year":1995,"finding":"IGF-II reduces programmed cell death (apoptosis) in skeletal muscle myoblasts both in vivo and in vitro, demonstrating a survival/anti-apoptotic function for IGF-II in muscle.","method":"Primary mdx and C57Bl muscle cell cultures; in vivo mouse models; apoptosis assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — both in vitro and in vivo evidence with functional readout","pmids":["17180029"],"is_preprint":false},{"year":1999,"finding":"Hypoxia induces IGF2 transcription from the P3 promoter in HepG2 cells through enhanced DNA-binding activity and increased expression of the transcription factor Egr-1; deletion of Egr-1 binding sites in the IGF2 P3 promoter abolishes hypoxic induction, and WT1 (a repressor) is simultaneously downregulated.","method":"Luciferase reporter assays, EMSA/supershift, RT-PCR, Western blot, Egr-1 cotransfection and promoter deletion analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted transcriptional activation with promoter deletion and co-transfection, multiple orthogonal methods","pmids":["10606246"],"is_preprint":false},{"year":2000,"finding":"A CTCF-binding element upstream of H19 acts as an enhancer-blocking insulator controlling imprinted Igf2 expression; methylation of CpGs within CTCF-binding sites abolishes CTCF binding in vitro, and deletion of these sites eliminates enhancer-blocking activity in vivo, allowing biallelic Igf2 expression. Insulator activity is restricted to the maternal allele by paternal allele DNA methylation.","method":"In vitro CTCF binding assays with methylated/unmethylated substrates; deletion mutant transfection enhancer-blocking assays; allele-specific expression","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding assay plus in vivo functional deletion, multiple orthogonal methods, widely replicated","pmids":["10839546"],"is_preprint":false},{"year":2001,"finding":"CpG methylation of the H19 imprinting control region (ICR) attenuates its CTCF-dependent insulator function; methylated ICR propagates stably in episomes, lacks nuclease hypersensitive sites, and fails to block enhancer-promoter communication, providing experimental support that methylation controls insulator activity.","method":"Episomal methylation propagation, nuclease sensitivity assay, insulator function assay in transfected Hep3B cells","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct functional test with methylated versus unmethylated substrates, multiple assays","pmids":["11509237"],"is_preprint":false},{"year":2002,"finding":"Most known enhancers for Igf2 are located 3' of H19; a radiation-induced inversion (minute mutation) whose breakpoint disrupts a mesodermal enhancer downstream of H19 causes drastic downregulation of Igf2 in all mesodermal tissues and placenta upon paternal transmission, establishing the positions of mesodermal and extra-embryonic enhancers for Igf2.","method":"Genetic characterization of radiation-induced inversion; allele-specific expression analysis; maternal transmission effects on H19 DMR methylation","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic mapping of regulatory elements, multiple tissue analysis","pmids":["11923202"],"is_preprint":false},{"year":2003,"finding":"mTOR and amino acid sufficiency regulate IGF-II transcription through IGF2 promoter 3 and a downstream enhancer during C2C12 myoblast differentiation; mTOR's function in initiating differentiation targets IGF production (not IGF signaling), and this is independent of mTOR kinase activity but mediated by the PI3K-Akt pathway.","method":"Promoter-reporter assays, mTOR inhibition (rapamycin), PI3K-Akt pathway dissection, C2C12 myoblast differentiation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple pharmacological and genetic dissections, in vitro functional readouts","pmids":["14662739"],"is_preprint":false},{"year":2004,"finding":"The oncogenic transcription factor PLAG1 is amplified and overexpressed in hepatoblastoma and transactivates IGF2 from the embryonic P3 promoter, providing a mechanism for IGF2 upregulation in this tumor type.","method":"Luciferase reporter assay (PLAG1 transactivation of IGF2 P3), real-time RT-PCR, comparative genomic hybridization","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter assay establishing transactivation, replicated in multiple hepatoblastoma cell lines","pmids":["14695992"],"is_preprint":false},{"year":2006,"finding":"CTCF mediates interchromosomal colocalization between the Igf2/H19 imprinting control region on chromosome 7 and Wsb1/Nf1 on chromosome 11; omission of CTCF or deletion of the maternal ICR abrogates this association and alters Wsb1/Nf1 gene expression, demonstrating CTCF-mediated long-range interchromosomal gene regulation.","method":"Modified chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — 3C and FISH with functional validation via CTCF omission and ICR deletion","pmids":["16614224"],"is_preprint":false},{"year":2006,"finding":"Increased Igf2 allelic dosage (biallelic expression via H19 maternal allele disruption) in Apc(Min/+) mice elongates intestinal crypts and increases adenoma growth independently of systemic growth; a soluble form of IGF-II/mannose-6-phosphate receptor (sIGF2R) acting as an IGF-II ligand trap rescues this phenotype, demonstrating functional potency of IGF2 epigenetic dosage in intestinal cancer.","method":"Mouse genetic crosses (Igf2 null, biallelic, monoallelic), sIGF2R transgene expression, intestinal crypt and adenoma measurements, nuclear beta-catenin staining","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple allelic dosage conditions tested in vivo, rescued by ligand-specific trap","pmids":["16488992"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of IGF2R domains 11-12-13/IGF-II complex reveal that IGF-II Phe19 and Leu53 lock into a hydrophobic pocket unique to domain 11 of mammalian IGF2R; domain 13 modulates binding site flexibility. Mutagenesis confirms this 'binding hotspot' and shows that IGFBP and IGF2R have converged on the same high-affinity IGF-II binding site.","method":"X-ray crystallography (crystal structures of IGF2R domains 11-12, 11-12-13-14, and 11-12-13/IGF-II complex), site-directed mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation, high-resolution mechanistic detail","pmids":["18046459"],"is_preprint":false},{"year":2008,"finding":"IGF2 activates PI3K/Akt and TGFβ signaling pathways in chondrocytes; PI3K-selective inhibitor LY294002 blocks Akt/GSK3β phosphorylation and abolishes IGF2-driven transcriptional upregulation of proteoglycans (Aggrecan and Versican), but does not suppress IGF2-induced TGFβ upregulation, indicating two independent signaling arms.","method":"Microarray gene expression analysis, Western blot (Akt, GSK3β phosphorylation), PI3K inhibitor (LY294002) experiments in C28/I2 chondrocyte cells","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological dissection with two pathway readouts, in vitro chondrocyte model","pmids":["18675921"],"is_preprint":false},{"year":2009,"finding":"Cohesin is required for CTCF-mediated higher-order chromatin conformation at the IGF2-H19 locus; RNAi-mediated cohesin depletion disrupts allele-specific chromatin looping and coincides with changes in IGF2 expression; this conformation exists in both G1 and G2 phases, independent of cohesin's sister chromatid cohesion function.","method":"Chromosome conformation capture (3C), RNAi cohesin depletion, cell-cycle phase analysis, allele-specific expression","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — 3C with RNAi knockdown and expression readout, cell-cycle independence demonstrated","pmids":["19956766"],"is_preprint":false},{"year":2011,"finding":"In rats, IGF-II enhances memory retention and prevents forgetting when injected into the hippocampus; learning-induced hippocampal IGF-II expression requires the transcription factor C/EBPβ and is essential for memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, ARC function, and GSK3; it correlates with GSK3β activation and increased GluR1/GRIA1 AMPA receptor subunit expression. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent persistent LTP after weak stimulation.","method":"Intrahippocampal recombinant IGF-II injection, inhibitory avoidance learning, receptor antagonists, protein synthesis inhibitors, hippocampal slice LTP, Western blot","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple pharmacological and behavioral methods, both in vivo and ex vivo validation","pmids":["21270887"],"is_preprint":false},{"year":2011,"finding":"Endostatin inhibits IGF-II-induced migration and invasion of extravillous trophoblasts but not proliferation; endostatin interferes with IGF-II-activated downstream signaling kinases ERK1/2, Akt/mTOR/p70S6K, and focal adhesion kinase. Akt1-specific silencing demonstrates that endostatin-mediated inhibition of IGF-II-induced Akt phosphorylation is critically dependent on Akt1 isoform expression.","method":"Transwell migration/invasion assays, villous explant cultures, kinase Western blots, Akt1 shRNA silencing in SGHPL-5 trophoblast cells","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — isoform-specific knockdown with functional and signaling readouts","pmids":["21933871"],"is_preprint":false},{"year":2012,"finding":"Autocrine IGF2/IGF1R signaling in cancer-associated fibroblasts (CAFs) induces myofibroblast differentiation (α-SMA expression and gel contractility); paracrine IGF2 from CAFs activates pro-survival AKT signaling in colorectal cancer cells via IGF1R/insulin receptor axis; IGF2-mediated physical matrix remodeling by CAFs (not secreted factors) facilitates tumor cell invasion in organotypic co-cultures.","method":"CAF co-culture, IGF2 knockdown, AKT signaling Western blot, floating collagen gel contractility, organotypic invasion assay, xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary in vitro and in vivo assays with genetic knockdown and functional rescue","pmids":["28534511"],"is_preprint":false},{"year":2012,"finding":"Akt1 and Igf2 null mutations independently decrease placental weight, fetal weight, and viability in mice; disruption of Igf2 does not affect AKT expression or activation, suggesting IGF2 acts upstream through additional effectors; Igf2 loss has more severe impact on prenatal survival and postnatal growth than Akt1 loss, with IGF2 contributing more to post-weaning growth.","method":"Genetic null mouse models (Akt1-/- and Igf2-/-) on CD1 background; placental, fetal, and postnatal growth phenotyping; AKT Western blot","journal":"The International journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — side-by-side genetic comparison on matched background with multiple phenotypic readouts","pmids":["22562201"],"is_preprint":false},{"year":2012,"finding":"Loss of p53 function creates Igf2 pathway dependency in vivo: developmental lethality occurs in p53 null mice lacking the paternal Igf2 allele; conditional Igf2 deletion attenuates rapid tumor onset in p53 null mice; biallelic Igf2 expression accelerates carcinoma/sarcoma formation in p53+/- females with reductions in p53 LOH and apoptosis.","method":"Conditional and germline Igf2/p53 double mutant mouse models; tumor incidence; gene expression profiling; apoptosis assays","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic combinations in vivo, epistasis established by compound mutants","pmids":["22674894"],"is_preprint":false},{"year":2013,"finding":"An intronic miRNA, miR-483-5p, embedded within IGF2 acts in a positive feedback loop by binding the 5'UTR of fetal IGF2 mRNA in the nucleus, enhancing the association of RNA helicase DHX9 with the IGF2 transcript, and promoting IGF2 transcription from fetal promoters; miR-483-5p is specifically overexpressed in Wilms' tumors and its ectopic expression increases tumorigenesis in IGF2-dependent sarcoma cells in vivo.","method":"miRNA screen in Wilms' tumors, nuclear miRNA pulldown, DHX9 co-association assay, promoter-specific transcription assays, in vivo tumorigenesis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — nuclear miRNA-mRNA interaction established with multiple orthogonal methods, in vivo functional validation","pmids":["24298054"],"is_preprint":false},{"year":2013,"finding":"5-Aza-2'deoxycytidine-induced demethylation of the H19 ICR in choriocarcinoma cells increases CTCF and cohesin recruitment, alters histone modifications, and reshapes chromatin looping such that a CTCF site downstream of H19 enhancers switches its association from the CTCF site upstream of IGF2 promoters to the ICR; a stable chromatin looping domain containing IGF2, marked by H3K27me3, forms independently of DNA methylation.","method":"5-AzaCdR treatment, CTCF/cohesin ChIP, histone modification ChIP, chromosome conformation capture (3C), allele-specific expression","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — multiple chromatin assays showing mechanistic link between methylation and topology","pmids":["23585276"],"is_preprint":false},{"year":2015,"finding":"β-cell-specific inactivation of Igf2 in mice (βIGF2KO) reveals that autocrine IGF2 regulates adult β-cell mass and function: βIGF2KO mice show reduced glucose-stimulated insulin secretion in aged females, impaired β-cell mass expansion during pregnancy and acute insulin resistance, and blunted β-cell proliferation, demonstrating that IGF2 produced and secreted by β-cells autocrinally activates IGF-1 receptor signaling.","method":"β-cell conditional Igf2 knockout mice; GSIS assays; glucose tolerance tests; β-cell mass morphometry; pregnancy and high-fat diet challenges","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — conditional knockout with multiple physiological challenges and functional readouts","pmids":["26384384"],"is_preprint":false},{"year":2015,"finding":"IGF2 protein functions are mediated through IGF-1R and the insulin receptor isoform A (IR-A); IGF-2 activates Akt phosphorylation and GSK3β phosphorylation, induces β-catenin levels, and protects ALS patient-derived motor neurons from degeneration; AAV9-delivered IGF-2 to muscles of SOD1(G93A) ALS mice extended lifespan by 10% while preserving motor neurons and inducing motor axon regeneration.","method":"IGF-2 addition to patient motor neuron cultures, Akt/GSK3β Western blot, AAV9 muscle delivery in SOD1(G93A) mice, motor neuron counting, neuromuscular junction analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro signaling combined with in vivo gene delivery with functional phenotypic readouts","pmids":["27180807"],"is_preprint":false},{"year":2016,"finding":"NF-κB activated by HER2/HER3 signaling targets IGF2 as a key downstream effector to promote tumor sphere formation in breast cancer; IGF2-PI3K signaling induces expression of the stemness transcription factor ID1, which in turn drives further IGF2 expression, forming a positive feedback loop (IGF2-ID1-IGF2 circuit) maintaining breast cancer stem-like cells; anti-IGF1/2 antibodies block tumorigenesis from IGF1Rhigh CSC populations in patient-derived xenografts.","method":"ID1 knockdown, IGF2 knockdown, NF-κB inhibition, anti-IGF1/2 antibody treatment, tumor sphere formation assay, patient-derived xenograft model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — genetic knockdowns and antibody blockade with functional rescue, in vivo xenograft validation","pmids":["27546618"],"is_preprint":false},{"year":2016,"finding":"Paternal Igf2 is specifically expressed in adult hematopoietic stem cells (HSCs); Igf2 deficiency prevents age-related attrition of the HSC pool and is necessary for tissue homeostasis and regeneration, indicating that Igf2 expression level is critical to maintain the balance between HSC self-renewal and differentiation.","method":"Igf2 null adult mouse analysis; HSC pool quantification by flow cytometry; transplantation assays; in situ expression analysis","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with quantitative HSC phenotyping and functional transplantation assays","pmids":["28007480"],"is_preprint":false},{"year":2019,"finding":"Hypomethylation of an enhancer within the IGF2 gene in prefrontal cortex neurons of schizophrenia and bipolar disorder patients is associated with increased tyrosine hydroxylase (TH) protein levels; chromatin conformation analysis shows this IGF2 enhancer contacts the TH gene promoter; mouse Igf2 enhancer deletion disrupts TH protein levels, striatal dopamine, and neuronal transcriptomic/proteomic organization.","method":"Neuron-specific DNA methylation profiling, chromatin conformation capture, proteomics, mouse Igf2 enhancer deletion, TH Western blot, dopamine measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multi-omics convergence plus mouse enhancer deletion with molecular and neurochemical phenotypes","pmids":["31053723"],"is_preprint":false},{"year":2020,"finding":"Hippocampal CIM6P/IGF2R (cation-independent mannose-6-phosphate/IGF2 receptor) is necessary for memory consolidation but not learning, retrieval, or reconsolidation; CIM6P/IGF2R controls training-induced upregulation of de novo protein synthesis (Arc, Egr1, c-Fos) without affecting their mRNA induction; hippocampal or systemic mannose-6-phosphate administration enhances memory in a CIM6P/IGF2R-dependent manner.","method":"CIM6P/IGF2R pharmacological inhibition in rats, neuron-specific Cre knockdown in mice, protein synthesis measurement, Western blot for IEG proteins vs. mRNA, behavioral memory assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — pharmacological and genetic inhibition converge on same phenotype with mechanistic protein synthesis readout","pmids":["32369018"],"is_preprint":false},{"year":2020,"finding":"IGF-II acts through both IGF-1R and insulin receptor isoform A (IR-A); mature and 'big' IGF-II exhibit similar activation of IR-A and IR-B signaling, while pro-IGF-II exhibits significantly less activation; downstream Akt activation by mature and 'big' IGF-II is greater in IR-A than IR-B cells, consistent with greater IR-A affinity for IGF-II.","method":"IGF-II isoform fractionation from human plasma, signaling assays in IGF-IR-deficient cells expressing IR-A or IR-B, Akt Western blot","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — isotype-specific receptor cell lines with quantitative signaling readouts","pmids":["21285309"],"is_preprint":false},{"year":2021,"finding":"Circadian master regulators Per1 and Per2 are required for proper myoblast differentiation and muscle regeneration; Per1 and Per2 activate Igf2 transcription by recruiting RNA polymerase II, enabling dynamic histone modifications, and establishing promoter-enhancer interactions at the Igf2 locus; muscle regeneration is faster when initiated at night when Per1, Per2, and Igf2 are maximally expressed.","method":"Per1/Per2 knockdown in myoblasts, in vivo muscle regeneration, ChIP for RNA Pol II and histone marks, chromatin conformation capture, circadian timing experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — chromatin-level mechanism validated in vitro and in vivo with circadian timing confirmation","pmids":["34009269"],"is_preprint":false},{"year":2022,"finding":"Hepatocyte-specific Igf2 deletion in SRSF3 knockout mice completely prevents hepatic fibrosis, inflammation, and tumor formation; in vitro, IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage, indicating that IGF2 overexpression promotes genomic instability and drives liver cancer.","method":"Double conditional knockout mice (Igf2/Srsf3); tumor incidence; DNA damage markers (γH2AX); DNA repair enzyme expression; IGF2 treatment of hepatoma cells in vitro","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 — double genetic deletion in vivo plus in vitro mechanistic confirmation with DNA damage readouts","pmids":["35615981"],"is_preprint":false},{"year":2023,"finding":"Hippocampal IGF2 is most highly expressed in pericytes; learning significantly increases pericytic Igf2 expression in the hippocampus in a neuronal activity-dependent manner; pericyte-specific (but not fibroblast- or neuron-specific) Igf2 knockout impairs long-term memory and blunts learning-dependent neuronal immediate early gene (IEG) induction, establishing a neuronal activity → pericyte IGF2 → neuron signaling axis required for long-term memory.","method":"Cell-type specific Igf2 knockout (pericyte, fibroblast, neuron), single-cell RNA-seq, activity-dependent expression measurement, behavioral memory tests, neuronal IEG Western blot","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific genetic knockouts with behavioral and molecular readouts, multiple controls","pmids":["37788670"],"is_preprint":false},{"year":2023,"finding":"Igf2 deletion in placental endocrine cells impairs placental endocrine signaling (including prolactin production) to the mother, reduces pregnancy-related insulin resistance, and restricts fetal growth and causes fetal hypoglycemia; Igf2 controls protein synthesis and cellular energy homeostasis in placental endocrine cells in a cell-type-dependent manner, and has long-lasting effects on offspring metabolism in adulthood.","method":"Placental endocrine cell-specific Igf2 knockout mice; placental hormone (prolactin) measurement; maternal insulin resistance testing; fetal growth and glucose measurement; protein synthesis and energy metabolism assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — conditional endocrine cell-specific deletion with multiple mechanistic and physiological readouts in vivo","pmids":["37437545"],"is_preprint":false}],"current_model":"IGF2 encodes a 67-amino acid secreted growth factor (processed from a 180-aa preproprotein) that signals primarily through IGF-1R and insulin receptor isoform A (IR-A) to activate PI3K/Akt, GSK3β, and MAPK pathways; its imprinted paternal-only expression is maintained by allele-specific DNA methylation that controls CTCF/cohesin-dependent chromatin insulation and enhancer access at the H19-IGF2 locus; its translation is regulated post-transcriptionally by mTOR/p70S6K; it acts as an autocrine/paracrine mitogen in fetal growth, β-cell mass adaptation, muscle regeneration (via Per1/Per2-dependent circadian epigenetic priming), and adult hematopoietic stem cell maintenance, and functions in the brain as a pericyte-derived, learning-induced signal required for long-term memory consolidation via CIM6P/IGF2R-dependent protein synthesis control."},"narrative":{"teleology":[{"year":1978,"claim":"Establishing the primary identity of IGF-II as a distinct insulin-family peptide resolved the molecular basis of non-suppressible insulin-like activity in serum and enabled all subsequent functional studies.","evidence":"Protein purification and amino acid sequencing from human serum","pmids":["658418"],"confidence":"High","gaps":["Post-translational processing pathway not yet elucidated","Receptor identity unknown","Genomic organization unknown"]},{"year":1984,"claim":"cDNA cloning revealed IGF2 is synthesized as a 180-aa preproprotein with an 89-aa E-peptide, defining the precursor-to-mature processing step and linking IGF2 to the insulin gene family.","evidence":"cDNA cloning and sequencing from human adult liver mRNA","pmids":["6382021","6382022"],"confidence":"High","gaps":["Proprotein convertase(s) responsible for E-peptide cleavage not identified","Biological activity of E-peptide unknown"]},{"year":1993,"claim":"Demonstrating monoallelic paternal expression of IGF2 in normal tissues and biallelic expression (loss of imprinting) in Wilms' tumors established epigenetic deregulation as a cancer mechanism, opening the imprinting field to oncology.","evidence":"Allele-specific RT-PCR using exonic polymorphisms in human tumor and normal tissue cohorts","pmids":["8385745"],"confidence":"High","gaps":["Molecular mechanism enforcing monoallelic silencing not yet identified","Causality of LOI in tumorigenesis versus bystander effect unresolved"]},{"year":1995,"claim":"Enhancer deletion and transgenic studies together established that IGF2 acts as both a local mitogen increasing cell number and a systemic growth factor controlling prenatal body size through shared enhancers 3′ of H19.","evidence":"Targeted enhancer deletion by homologous recombination in mice; keratin-driven Igf2 transgenic mice with tissue DNA content and growth measurements","pmids":["7524092","7544754"],"confidence":"High","gaps":["Identity of tissue-specific enhancers beyond endoderm not mapped","Relative contributions of IGF-1R versus other receptors in fetal growth unknown"]},{"year":1995,"claim":"Discovery that IGF2 mRNA is stored in untranslated 100S ribonucleoprotein particles and mobilized via the mTOR/p70S6K pathway revealed a post-transcriptional control layer linking nutrient sensing to IGF2 protein output.","evidence":"Sucrose gradient sedimentation, rapamycin/anisomycin pharmacological inhibition, polysome profiling","pmids":["7566093"],"confidence":"High","gaps":["RNA-binding proteins composing the 100S particle not identified","Cis-regulatory elements in IGF2 mRNA mediating translational repression unknown"]},{"year":2000,"claim":"Identification of the CTCF-dependent enhancer-blocking insulator at the H19 ICR, silenced on the paternal allele by CpG methylation, provided the mechanistic basis for allele-specific IGF2 expression and linked DNA methylation directly to chromatin insulator function.","evidence":"In vitro CTCF binding assays with methylated/unmethylated DNA; in vivo deletion of CTCF sites; episomal methylation propagation and insulator assays","pmids":["10839546","11509237"],"confidence":"High","gaps":["How methylation is established and maintained at the paternal ICR during development not fully resolved","Contribution of individual CTCF sites versus cluster not dissected"]},{"year":2006,"claim":"Biallelic IGF2 expression in Apc(Min/+) mice accelerated intestinal adenoma growth and was rescued by a soluble IGF2R ligand trap, directly establishing IGF2 epigenetic dosage as a functional driver in intestinal tumorigenesis.","evidence":"Allelic dosage genetic crosses with Apc(Min/+); sIGF2R transgene rescue; intestinal crypt and adenoma measurements","pmids":["16488992"],"confidence":"High","gaps":["Whether IGF2 acts on tumor cells, stroma, or both in this context not resolved","Therapeutic window for IGF2R-based ligand trapping not defined"]},{"year":2007,"claim":"Crystal structures of IGF2R domains 11-13 in complex with IGF-II revealed the hydrophobic binding pocket (Phe19, Leu53) for clearance/signaling via the mannose-6-phosphate receptor, showing convergent evolution with IGFBPs on the same IGF-II surface.","evidence":"X-ray crystallography of IGF2R domain complexes with site-directed mutagenesis validation","pmids":["18046459"],"confidence":"High","gaps":["Full-length IGF2R structure and mechanism of IGF-II internalization/degradation not resolved","How domain 13 flexibility modulates affinity in vivo unknown"]},{"year":2009,"claim":"Cohesin was shown to be required for CTCF-mediated chromatin looping at the IGF2-H19 locus independently of its cohesion function, establishing the architectural co-dependence of CTCF and cohesin in imprinting control.","evidence":"3C and RNAi-mediated cohesin depletion with allele-specific expression readout, cell-cycle phase analysis","pmids":["19956766"],"confidence":"High","gaps":["Whether cohesin loading at the ICR requires CTCF directly or other factors not determined","Impact of cohesin mutations on IGF2 imprinting in human disease not tested"]},{"year":2011,"claim":"Intrahippocampal IGF-II injection enhanced memory consolidation and promoted persistent LTP through IGF2R (not IGF-1R), GSK3β, and de novo protein synthesis, establishing a cognitive function for IGF2 beyond its classical growth role.","evidence":"Recombinant IGF-II hippocampal injection, inhibitory avoidance learning, receptor antagonists, protein synthesis inhibitors, hippocampal slice electrophysiology","pmids":["21270887"],"confidence":"High","gaps":["Cellular source of endogenous hippocampal IGF2 not identified at this point","Downstream translational targets mediating memory enhancement not catalogued"]},{"year":2013,"claim":"Discovery of a positive feedback loop in which the intronic miR-483-5p binds the 5′UTR of IGF2 mRNA in the nucleus and recruits RNA helicase DHX9 to enhance IGF2 transcription revealed an embedded cis-regulatory amplification circuit overexpressed in Wilms' tumor.","evidence":"Nuclear miRNA pulldown, DHX9 co-association assay, promoter-specific transcription assays, in vivo tumorigenesis in sarcoma model","pmids":["24298054"],"confidence":"High","gaps":["Whether miR-483-5p feedback operates in non-tumor tissues unknown","Structural basis of 5′UTR recognition by miR-483-5p not resolved"]},{"year":2015,"claim":"β-cell-specific Igf2 knockout demonstrated that autocrine IGF2/IGF-1R signaling is required for adaptive β-cell mass expansion during pregnancy and insulin resistance, extending IGF2's role to metabolic adaptation in adults.","evidence":"Conditional β-cell Igf2 knockout mice with GSIS assays, glucose tolerance tests, β-cell morphometry under pregnancy and high-fat diet challenges","pmids":["26384384"],"confidence":"High","gaps":["Whether human β-cells maintain IGF2 expression to the same extent as mouse not established","Downstream transcriptional program in β-cells not characterized"]},{"year":2021,"claim":"Per1/Per2 were found to recruit RNA Pol II and enable promoter-enhancer looping at the Igf2 locus, linking circadian regulation to muscle regeneration timing and explaining why regeneration is faster at circadian peaks of Igf2 expression.","evidence":"Per1/Per2 knockdown in myoblasts, in vivo muscle regeneration, ChIP for Pol II and histone marks, 3C, circadian timing experiments","pmids":["34009269"],"confidence":"High","gaps":["Whether other clock genes participate in Igf2 regulation not tested","Mechanism by which Per proteins recruit Pol II to Igf2 promoters not elucidated"]},{"year":2023,"claim":"Cell-type-specific knockouts identified pericytes as the critical hippocampal source of learning-induced IGF2 that signals to neurons to promote IEG-dependent protein synthesis for long-term memory, completing a neurovascular signaling circuit (neuronal activity → pericyte IGF2 → neuron).","evidence":"Pericyte-, fibroblast-, and neuron-specific Igf2 knockout; scRNA-seq; behavioral memory tests; neuronal IEG protein measurement","pmids":["37788670"],"confidence":"High","gaps":["Receptor (IGF2R vs. IGF-1R) mediating pericyte-to-neuron signaling not definitively resolved in this context","Mechanism of neuronal activity sensing by pericytes unknown"]},{"year":2023,"claim":"Placental endocrine cell-specific Igf2 deletion revealed that IGF2 controls protein synthesis and energy homeostasis within the placenta and orchestrates maternal metabolic adaptation (insulin resistance, prolactin), establishing IGF2 as a master regulator of the feto-maternal metabolic dialogue.","evidence":"Placental endocrine cell-specific Igf2 knockout mice with placental hormone, maternal insulin resistance, fetal glucose, and protein synthesis measurements","pmids":["37437545"],"confidence":"High","gaps":["Whether IGF2 acts via IGF-1R or IR-A in placental endocrine cells not resolved","How placental IGF2 programs offspring adult metabolism remains mechanistically open"]},{"year":null,"claim":"Key open questions include the structural basis of differential IGF2 signaling through IGF-1R versus IR-A, the identity of the translational repression complex sequestering IGF2 mRNA, how neuronal activity is communicated to pericytes to induce IGF2, and whether IGF2 LOI is sufficient to initiate (rather than accelerate) tumorigenesis independently of cooperating mutations.","evidence":"","pmids":[],"confidence":"High","gaps":["No IGF2/IGF-1R co-crystal structure available","RNA-binding proteins in the 100S storage particle unidentified","Pericyte activity-sensing mechanism unknown","Causality of LOI alone in tumor initiation not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4,19,26,27,35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,23,28]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4,5,26,35,36]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,22,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,15,23,24,28,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,19,20,27,28,32]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,26]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[19,30,31,35]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,8,9,13,24,33]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,10,14,18,25]}],"complexes":[],"partners":["IGF1R","INSR","IGF2R","CTCF","PER1","PER2","DHX9","PLAG1"],"other_free_text":[]},"mechanistic_narrative":"IGF2 encodes a paternally imprinted, secreted 67-amino-acid mitogenic peptide (processed from a 180-aa preproprotein) that signals through IGF-1R and insulin receptor isoform A (IR-A) to activate PI3K/Akt/GSK3β and MAPK pathways, functioning as an autocrine/paracrine growth factor in fetal development, placental endocrine signaling, β-cell mass regulation, muscle regeneration, and long-term memory consolidation [PMID:658418, PMID:6382021, PMID:26384384, PMID:37788670, PMID:37437545]. Monoallelic paternal expression is enforced by allele-specific DNA methylation of the H19 imprinting control region, which governs CTCF/cohesin-dependent chromatin insulation and enhancer access; loss of imprinting leading to biallelic expression drives overexpression in Wilms' tumor, intestinal adenoma, and other cancers [PMID:10839546, PMID:19956766, PMID:8385745, PMID:16488992]. IGF2 translation is post-transcriptionally regulated by the mTOR/p70S6K pathway, and its transcription is controlled by circadian regulators Per1/Per2, hypoxia-responsive Egr-1, and the oncogenic factor PLAG1 [PMID:7566093, PMID:34009269, PMID:10606246, PMID:14695992]. In the hippocampus, pericyte-derived IGF2 acts through CIM6P/IGF2R to promote de novo protein synthesis required for long-term memory consolidation [PMID:37788670, PMID:32369018, PMID:21270887]."},"prefetch_data":{"uniprot":{"accession":"P01344","full_name":"Insulin-like growth factor 2","aliases":["Insulin-like growth factor II","IGF-II","Somatomedin-A","T3M-11-derived growth factor"],"length_aa":180,"mass_kda":20.1,"function":"The insulin-like growth factors possess growth-promoting activity (By similarity). Major fetal growth hormone in mammals. Plays a key role in regulating fetoplacental development. IGF2 is influenced by placental lactogen. Also involved in tissue differentiation. In adults, involved in glucose metabolism in adipose tissue, skeletal muscle and liver (Probable). Acts as a ligand for integrin which is required for IGF2 signaling (PubMed:28873464). Positively regulates myogenic transcription factor MYOD1 function by facilitating the recruitment of transcriptional coactivators, thereby controlling muscle terminal differentiation (By similarity). Inhibits myoblast differentiation and modulates metabolism via increasing the mitochondrial respiration rate (By similarity) Preptin undergoes glucose-mediated co-secretion with insulin, and acts as a physiological amplifier of glucose-mediated insulin secretion. Exhibits osteogenic properties by increasing osteoblast mitogenic activity through phosphoactivation of MAPK1 and MAPK3","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P01344/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IGF2","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IGF2","total_profiled":1310},"omim":[{"mim_id":"619489","title":"SHORT STATURE, DAUBER-ARGENTE TYPE; SSDA","url":"https://www.omim.org/entry/619489"},{"mim_id":"618908","title":"SILVER-RUSSELL SYNDROME 5; SRS5","url":"https://www.omim.org/entry/618908"},{"mim_id":"618907","title":"SILVER-RUSSELL SYNDROME 4; SRS4","url":"https://www.omim.org/entry/618907"},{"mim_id":"618905","title":"SILVER-RUSSELL SYNDROME 2; SRS2","url":"https://www.omim.org/entry/618905"},{"mim_id":"618743","title":"PHOSPHOLIPID PHOSPHATASE 7; PLPP7","url":"https://www.omim.org/entry/618743"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":2597.9}],"url":"https://www.proteinatlas.org/search/IGF2"},"hgnc":{"alias_symbol":["FLJ44734","IGF-II"],"prev_symbol":["C11orf43"]},"alphafold":{"accession":"P01344","domains":[{"cath_id":"1.10.100.10","chopping":"34-55_63-86","consensus_level":"medium","plddt":58.5,"start":34,"end":86},{"cath_id":"1.20.5","chopping":"117-154","consensus_level":"medium","plddt":67.8082,"start":117,"end":154}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01344","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01344-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01344-F1-predicted_aligned_error_v6.png","plddt_mean":59.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IGF2","jax_strain_url":"https://www.jax.org/strain/search?query=IGF2"},"sequence":{"accession":"P01344","fasta_url":"https://rest.uniprot.org/uniprotkb/P01344.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01344/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01344"}},"corpus_meta":[{"pmid":"10839546","id":"PMC_10839546","title":"Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.","date":"2000","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10839546","citation_count":1371,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16614224","id":"PMC_16614224","title":"CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.","date":"2006","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/16614224","citation_count":377,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7544754","id":"PMC_7544754","title":"An enhancer deletion affects both H19 and Igf2 expression.","date":"1995","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7544754","citation_count":348,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21270887","id":"PMC_21270887","title":"A critical role for IGF-II in memory consolidation and enhancement.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21270887","citation_count":333,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18308616","id":"PMC_18308616","title":"IGF2: epigenetic regulation and role in development and disease.","date":"2008","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/18308616","citation_count":259,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24080445","id":"PMC_24080445","title":"IGF2 and cancer.","date":"2013","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24080445","citation_count":250,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9722981","id":"PMC_9722981","title":"Insulin-like growth factor II (IGF-II).","date":"1998","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9722981","citation_count":232,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23671155","id":"PMC_23671155","title":"Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive.","date":"2013","source":"Endocrine reviews","url":"https://pubmed.ncbi.nlm.nih.gov/23671155","citation_count":171,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18587395","id":"PMC_18587395","title":"Conservation of the H19 noncoding RNA and H19-IGF2 imprinting mechanism in therians.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18587395","citation_count":161,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26154720","id":"PMC_26154720","title":"Paternally Inherited IGF2 Mutation and Growth Restriction.","date":"2015","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26154720","citation_count":159,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7566093","id":"PMC_7566093","title":"Growth-dependent translation of IGF-II mRNA by a rapamycin-sensitive pathway.","date":"1995","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/7566093","citation_count":157,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10603082","id":"PMC_10603082","title":"Allelic expression of IGF2 in marsupials and birds.","date":"2000","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/10603082","citation_count":141,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24738971","id":"PMC_24738971","title":"Epigenetic regulation of the Igf2/H19 gene cluster.","date":"2014","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/24738971","citation_count":140,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24298054","id":"PMC_24298054","title":"The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis.","date":"2013","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/24298054","citation_count":132,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14662739","id":"PMC_14662739","title":"IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14662739","citation_count":123,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18794369","id":"PMC_18794369","title":"A novel H19 antisense RNA overexpressed in breast cancer contributes to paternal IGF2 expression.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18794369","citation_count":116,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16357124","id":"PMC_16357124","title":"Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16357124","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11479919","id":"PMC_11479919","title":"Monotreme IGF2 expression and ancestral origin of genomic imprinting.","date":"2001","source":"The Journal of experimental zoology","url":"https://pubmed.ncbi.nlm.nih.gov/11479919","citation_count":106,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9342054","id":"PMC_9342054","title":"Imprinting of Igf2 and H19 from a 130 kb YAC transgene.","date":"1997","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9342054","citation_count":99,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18046459","id":"PMC_18046459","title":"Structure and functional analysis of the IGF-II/IGF2R interaction.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/18046459","citation_count":98,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9285792","id":"PMC_9285792","title":"Imprinting of IGF2 and H19: lack of reciprocity in sporadic Beckwith-Wiedemann syndrome.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9285792","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18541649","id":"PMC_18541649","title":"Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18541649","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11689707","id":"PMC_11689707","title":"Regulatory mechanisms at the mouse Igf2/H19 locus.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11689707","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12493244","id":"PMC_12493244","title":"H19 and Igf2--enhancing the confusion?","date":"2003","source":"Trends in genetics : TIG","url":"https://pubmed.ncbi.nlm.nih.gov/12493244","citation_count":92,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12531883","id":"PMC_12531883","title":"A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinoma.","date":"2003","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/12531883","citation_count":87,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7524092","id":"PMC_7524092","title":"Disproportionate growth in mice with Igf-2 transgenes.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7524092","citation_count":86,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10606246","id":"PMC_10606246","title":"Egr-1 mediates transcriptional activation of IGF-II gene in response to hypoxia.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10606246","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27180807","id":"PMC_27180807","title":"Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27180807","citation_count":84,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14695992","id":"PMC_14695992","title":"Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma.","date":"2004","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/14695992","citation_count":81,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25719943","id":"PMC_25719943","title":"Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway.","date":"2015","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/25719943","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35741015","id":"PMC_35741015","title":"IGF2: Development, Genetic and Epigenetic Abnormalities.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35741015","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22926517","id":"PMC_22926517","title":"miR-100 suppresses IGF2 and inhibits breast tumorigenesis by interfering with proliferation and survival signaling.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22926517","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10729220","id":"PMC_10729220","title":"Symmetric and asymmetric DNA methylation in the human IGF2-H19 imprinted region.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10729220","citation_count":71,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22136428","id":"PMC_22136428","title":"Biology and significance of signalling pathways activated by IGF-II.","date":"2011","source":"Growth factors (Chur, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/22136428","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10761859","id":"PMC_10761859","title":"Igf2 imprinting in development and disease.","date":"2000","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10761859","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33407516","id":"PMC_33407516","title":"Hypoxia downregulated miR-4521 suppresses gastric carcinoma progression through regulation of IGF2 and FOXM1.","date":"2021","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33407516","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11509237","id":"PMC_11509237","title":"CpG methylation regulates the Igf2/H19 insulator.","date":"2001","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/11509237","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17325430","id":"PMC_17325430","title":"Loss of imprinting of IGF2 as an epigenetic marker for the risk of human cancer.","date":"2007","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/17325430","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28534511","id":"PMC_28534511","title":"Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28534511","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9570364","id":"PMC_9570364","title":"Biallelic expression of the H19 and IGF2 genes in hepatocellular carcinoma.","date":"1997","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/9570364","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31623387","id":"PMC_31623387","title":"Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer-From Basic Research to Potential Clinical Applications.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31623387","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37031050","id":"PMC_37031050","title":"IGF2 in memory, neurodevelopmental disorders, and neurodegenerative diseases.","date":"2023","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/37031050","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31590432","id":"PMC_31590432","title":"The Neglected Insulin: IGF-II, a Metabolic Regulator with Implications for Diabetes, Obesity, and Cancer.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31590432","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33053840","id":"PMC_33053840","title":"Understanding IGF-II Action through Insights into Receptor Binding and Activation.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33053840","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23257922","id":"PMC_23257922","title":"IGF2 mRNA binding protein p62/IMP2-2 in hepatocellular carcinoma: antiapoptotic action is independent of IGF2/PI3K signaling.","date":"2012","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23257922","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27546618","id":"PMC_27546618","title":"Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27546618","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37437545","id":"PMC_37437545","title":"Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene.","date":"2023","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/37437545","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8842730","id":"PMC_8842730","title":"Biallelic expression of the IGF2 gene in human breast disease.","date":"1996","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8842730","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16488992","id":"PMC_16488992","title":"Soluble IGF2 receptor rescues Apc(Min/+) intestinal adenoma progression induced by Igf2 loss of imprinting.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16488992","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9570380","id":"PMC_9570380","title":"Loss of imprinting and overexpression of IGF2 gene in gastric adenocarcinoma.","date":"1997","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/9570380","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10690526","id":"PMC_10690526","title":"Loss of imprinting of the IGF-II and H19 genes in epithelial ovarian cancer.","date":"2000","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/10690526","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31053723","id":"PMC_31053723","title":"Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31053723","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7717451","id":"PMC_7717451","title":"IGF2 expression is a marker for paraganglionic/SIF cell differentiation in neuroblastoma.","date":"1995","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7717451","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9062579","id":"PMC_9062579","title":"Association of IGF2 and H19 imprinting with choriocarcinoma development.","date":"1997","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/9062579","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26384384","id":"PMC_26384384","title":"Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function.","date":"2015","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/26384384","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21932422","id":"PMC_21932422","title":"Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal adenoma.","date":"2011","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21932422","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36672737","id":"PMC_36672737","title":"IGF2: A Role in Metastasis and Tumor Evasion from Immune Surveillance?","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/36672737","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26333472","id":"PMC_26333472","title":"DNA methylation in imprinted genes IGF2 and GNASXL is associated with prenatal maternal stress.","date":"2015","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/26333472","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3503697","id":"PMC_3503697","title":"Regulation of human IGF-II transcription in fetal and adult tissues.","date":"1987","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/3503697","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18946176","id":"PMC_18946176","title":"Identification of Igf2, Igfbp2 and Enpp2 as estrogen-responsive genes in rat hippocampus.","date":"2008","source":"Endocrine journal","url":"https://pubmed.ncbi.nlm.nih.gov/18946176","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21733157","id":"PMC_21733157","title":"Hepatoprotection and neuroprotection induced by low doses of IGF-II in aging rats.","date":"2011","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21733157","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17180029","id":"PMC_17180029","title":"Programmed cell death in dystrophic (mdx) muscle is inhibited by IGF-II.","date":"1995","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/17180029","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27681092","id":"PMC_27681092","title":"Current ideas on the biology of IGFBP-6: More than an IGF-II inhibitor?","date":"2016","source":"Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/27681092","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18675921","id":"PMC_18675921","title":"IGF2-driven PI3 kinase and TGFbeta signaling pathways in chondrogenesis.","date":"2008","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/18675921","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29604392","id":"PMC_29604392","title":"IGF2 induces CD133 expression in esophageal cancer cells to promote cancer stemness.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29604392","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17403010","id":"PMC_17403010","title":"IGF2 gene characterization and association with rib eye area in beef cattle.","date":"2007","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17403010","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28910276","id":"PMC_28910276","title":"IGF2 stimulates fetal growth in a sex- and organ-dependent manner.","date":"2017","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/28910276","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35154476","id":"PMC_35154476","title":"Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2.","date":"2022","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/35154476","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11923202","id":"PMC_11923202","title":"Disruption of mesodermal enhancers for Igf2 in the minute mutant.","date":"2002","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11923202","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9455791","id":"PMC_9455791","title":"Loss of imprinting of igf2 in renal-cell carcinomas.","date":"1998","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/9455791","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34009269","id":"PMC_34009269","title":"Per1/Per2-Igf2 axis-mediated circadian regulation of myogenic differentiation.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34009269","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35615981","id":"PMC_35615981","title":"Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35615981","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14624463","id":"PMC_14624463","title":"Epigenetic regulation of Igf2/H19 imprinting at CTCF insulator binding sites.","date":"2003","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14624463","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31544945","id":"PMC_31544945","title":"IGF2 Mutations.","date":"2020","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31544945","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32369018","id":"PMC_32369018","title":"A role for CIM6P/IGF2 receptor in memory consolidation and enhancement.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32369018","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22562201","id":"PMC_22562201","title":"Akt1 and insulin-like growth factor 2 (Igf2) regulate placentation and fetal/postnatal development.","date":"2012","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22562201","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22770937","id":"PMC_22770937","title":"IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy.","date":"2012","source":"Journal of diabetes and its complications","url":"https://pubmed.ncbi.nlm.nih.gov/22770937","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30231881","id":"PMC_30231881","title":"IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling.","date":"2018","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/30231881","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28007480","id":"PMC_28007480","title":"Paternal Insulin-like Growth Factor 2 (Igf2) Regulates Stem Cell Activity During Adulthood.","date":"2016","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/28007480","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22674894","id":"PMC_22674894","title":"Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes.","date":"2012","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22674894","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23935095","id":"PMC_23935095","title":"Autoimmunity against INS-IGF2 protein expressed in human pancreatic islets.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23935095","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23585276","id":"PMC_23585276","title":"Induced DNA demethylation can reshape chromatin topology at the IGF2-H19 locus.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23585276","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8957451","id":"PMC_8957451","title":"Variable imprinting of H19 and IGF2 in fetal cerebellum and medulloblastoma.","date":"1996","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/8957451","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21933871","id":"PMC_21933871","title":"Endostatin suppresses IGF-II-mediated signaling and invasion of human extravillous trophoblasts.","date":"2011","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21933871","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32033443","id":"PMC_32033443","title":"The IGF-II-Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32033443","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29484033","id":"PMC_29484033","title":"Is ZFP57 binding to H19/IGF2:IG-DMR affected in Silver-Russell syndrome?","date":"2018","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29484033","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23620526","id":"PMC_23620526","title":"The prevalence of loss of imprinting of H19 and IGF2 at birth.","date":"2013","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/23620526","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12804639","id":"PMC_12804639","title":"Loss of imprinting of IGF-II gene in children with acute lymphoblastic leukemia.","date":"2003","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/12804639","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27185872","id":"PMC_27185872","title":"IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis.","date":"2016","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27185872","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20042264","id":"PMC_20042264","title":"Expression of the imprinted IGF2 and H19 genes in the endometrium of cases with unexplained infertility.","date":"2009","source":"European journal of obstetrics, gynecology, and reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/20042264","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18237730","id":"PMC_18237730","title":"IGF-II is present in bovine corneal stroma and activates keratocytes to proliferate in vitro.","date":"2007","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/18237730","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32427884","id":"PMC_32427884","title":"Critical role of SOX2-IGF2 signaling in aggressiveness of bladder cancer.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32427884","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31608492","id":"PMC_31608492","title":"Effects of Sprifermin, IGF1, IGF2, BMP7, or CNP on Bovine Chondrocytes in Monolayer and 3D Culture.","date":"2019","source":"Journal of orthopaedic research : official publication of the Orthopaedic Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/31608492","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10738131","id":"PMC_10738131","title":"Genomic imprinting of IGF2 and H19 in human meningiomas.","date":"2000","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/10738131","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29017633","id":"PMC_29017633","title":"Associations between maternal prenatal stress, methylation changes in IGF1 and IGF2, and birth weight.","date":"2017","source":"Journal of developmental origins of health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/29017633","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33318299","id":"PMC_33318299","title":"IGF2 improves the developmental competency and meiotic structure of oocytes from aged mice.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33318299","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37788670","id":"PMC_37788670","title":"Neuronal activity drives IGF2 expression from pericytes to form long-term memory.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/37788670","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23023303","id":"PMC_23023303","title":"Cell type and context-specific function of PLAG1 for IGF2 P3 promoter activity.","date":"2012","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23023303","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21285309","id":"PMC_21285309","title":"Plasma distribution and signaling activities of IGF-II precursors.","date":"2011","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21285309","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27535174","id":"PMC_27535174","title":"Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas.","date":"2016","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27535174","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18955703","id":"PMC_18955703","title":"Persistent epigenetic differences associated with prenatal exposure to famine in humans.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18955703","citation_count":1901,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17554260","id":"PMC_17554260","title":"Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17554260","citation_count":1174,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8385745","id":"PMC_8385745","title":"Relaxation of imprinted genes in human cancer.","date":"1993","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8385745","citation_count":742,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"658418","id":"PMC_658418","title":"Primary structure of human insulin-like growth factor II.","date":"1978","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/658418","citation_count":712,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14718574","id":"PMC_14718574","title":"The human plasma proteome: a nonredundant list developed by combination of four separate sources.","date":"2004","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/14718574","citation_count":658,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8589713","id":"PMC_8589713","title":"Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome.","date":"1996","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8589713","citation_count":612,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12637750","id":"PMC_12637750","title":"Loss of IGF2 imprinting: a potential marker of colorectal cancer risk.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12637750","citation_count":565,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17632545","id":"PMC_17632545","title":"A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17632545","citation_count":422,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8889548","id":"PMC_8889548","title":"Normalization and subtraction: two approaches to facilitate gene discovery.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8889548","citation_count":401,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15797461","id":"PMC_15797461","title":"Insulin-like growth factor signaling in fish.","date":"2005","source":"International review of cytology","url":"https://pubmed.ncbi.nlm.nih.gov/15797461","citation_count":399,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12138094","id":"PMC_12138094","title":"Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12138094","citation_count":393,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19767753","id":"PMC_19767753","title":"Identification of seven new prostate cancer susceptibility loci through a genome-wide association study.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19767753","citation_count":348,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8939990","id":"PMC_8939990","title":"Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8939990","citation_count":340,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"6382021","id":"PMC_6382021","title":"Sequence of a cDNA clone encoding human preproinsulin-like growth factor II.","date":"1984","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/6382021","citation_count":337,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19924280","id":"PMC_19924280","title":"Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19924280","citation_count":329,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27869826","id":"PMC_27869826","title":"Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.","date":"2016","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27869826","citation_count":316,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17591929","id":"PMC_17591929","title":"Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.","date":"2007","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/17591929","citation_count":290,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28611215","id":"PMC_28611215","title":"Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28611215","citation_count":282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"6382022","id":"PMC_6382022","title":"Insulin-like growth factor II precursor gene organization in relation to insulin gene family.","date":"1984","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/6382022","citation_count":270,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19956766","id":"PMC_19956766","title":"Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19956766","citation_count":269,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15146197","id":"PMC_15146197","title":"Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.","date":"2004","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/15146197","citation_count":266,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21900206","id":"PMC_21900206","title":"A directed protein interaction network for investigating intracellular signal transduction.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46257,"output_tokens":7163,"usd":0.123108},"stage2":{"model":"claude-opus-4-6","input_tokens":10855,"output_tokens":4787,"usd":0.260925},"total_usd":0.785673,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58905,"output_tokens":8914,"usd":0.155213},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":13047,"output_tokens":3962,"usd":0.246427}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Methylation of CpG sites within CTCF-binding sites in the imprinting control region (ICR) upstream of H19 eliminates CTCF binding in vitro, abolishing enhancer-blocking (insulator) activity and allowing paternal-allele IGF2 expression; on the maternal allele, unmethylated CTCF sites permit CTCF binding and block enhancer access to IGF2, silencing it.\",\n      \"method\": \"CTCF binding assays in vitro with methylated vs. unmethylated oligonucleotides; deletion of CTCF-binding sites in vivo; transgenic and loss-of-function mouse models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (in vitro binding, deletion mutants, in vivo reporter), replicated by multiple subsequent studies\",\n      \"pmids\": [\"10839546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IGF2 and H19 share the same downstream endoderm-specific enhancers; deletion of these enhancers by targeted recombination abolishes H19 expression on maternal inheritance and IGF2 expression on paternal inheritance, establishing that the two genes compete for common enhancers on different parental chromosomes.\",\n      \"method\": \"Targeted enhancer deletion by homologous recombination in ES cells; RNA expression analysis in multiple tissues\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean genetic deletion with defined tissue-specific phenotypic readout, foundational study replicated by subsequent work\",\n      \"pmids\": [\"7544754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CTCF mediates interchromosomal colocalization between the Igf2/H19 imprinting control region on chromosome 7 and the Wsb1/Nf1 locus on chromosome 11; omission of CTCF or deletion of the maternal ICR abrogates this trans-chromosomal association and alters Wsb1/Nf1 gene expression.\",\n      \"method\": \"Modified chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH); CTCF knockdown and ICR deletion experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal methods (3C + FISH + genetic deletion) in a single rigorous study\",\n      \"pmids\": [\"16614224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of IGF2R domains 11-12-13 in complex with IGF-II show that domain 11 directly contacts IGF-II via a hydrophobic pocket engaging Phe19 and Leu53 of IGF-II, while domain 13 modulates binding-site flexibility; mutagenesis confirmed this as the IGF-II binding hotspot, and the same site is targeted by IGF-binding proteins.\",\n      \"method\": \"X-ray crystallography of IGF2R/IGF-II complex; site-directed mutagenesis of binding residues\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis validation in a single study\",\n      \"pmids\": [\"18046459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The major 6.0-kb IGF2 mRNA is stored untranslated in a 100S ribonucleoprotein particle and selectively mobilized and translated in exponentially growing cells; this translational activation is blocked by rapamycin and mimicked by anisomycin, implicating the p70S6K/85S6K kinase signaling pathway in growth-dependent IGF2 translation.\",\n      \"method\": \"Polysome fractionation; rapamycin and anisomycin pharmacological inhibition; metabolic labeling in cell culture\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical fractionation plus pharmacological dissection with multiple inhibitors\",\n      \"pmids\": [\"7566093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hippocampal IGF-II is required for memory consolidation after inhibitory avoidance learning in rats; exogenous IGF-II injection into hippocampus after training or retrieval enhances memory retention; the effect requires IGF-II receptors (IGF2R), new protein synthesis, ARC function, and GSK3 activity, and correlates with synaptic GSK3β activation and increased GluR1 AMPA receptor subunit expression.\",\n      \"method\": \"Intrahippocampal injection of recombinant IGF-II; pharmacological blockade (IGF2R antibody, protein synthesis inhibitors, GSK3 inhibitors); hippocampal slice LTP recordings; Western blot\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (behavioral pharmacology, electrophysiology, biochemistry) establishing pathway position\",\n      \"pmids\": [\"21270887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IGF-II transcription in skeletal myoblast differentiation is controlled by mTOR signaling through the IGF-II promoter 3 and a downstream enhancer; mTOR regulates IGF-II production (not IGF signaling) as the primary target for initiating differentiation, and this action is independent of mTOR kinase activity and mediated upstream by the PI3K-Akt pathway.\",\n      \"method\": \"Rapamycin treatment; IGF-II promoter-luciferase reporter assays; kinase-dead mTOR constructs; C2C12 myoblast differentiation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter reporter assays plus kinase-dead constructs plus pharmacological epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"14662739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Hypoxia transcriptionally activates IGF-II via the P3 promoter in HepG2 cells through increased Egr-1 expression and DNA binding activity; Egr-1 binding sites in the IGF-II P3 promoter are essential for this response, while the repressor WT1 is simultaneously decreased.\",\n      \"method\": \"Luciferase reporter assays with P3 promoter deletions; EMSA and supershift assays for Egr-1 binding; cotransfection of Egr-1 expression vector; mRNA stability assay; Western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — promoter deletion mapping, EMSA, and cotransfection epistasis in a single study\",\n      \"pmids\": [\"10606246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The transcription factor PLAG1, amplified in hepatoblastoma, transactivates transcription from the embryonic IGF2 P3 promoter; PLAG1 is overexpressed in hepatoblastoma and luciferase reporter assays confirm its direct activation of IGF2 P3 in hepatoblastoma cell lines.\",\n      \"method\": \"Luciferase reporter assays with IGF2 P3 promoter; quantitative RT-PCR; copy number analysis\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reporter assay plus expression correlation; single lab\",\n      \"pmids\": [\"14695992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The IGF2-intronic miR-483-5p forms a nuclear pool that binds directly to the 5'UTR of fetal IGF2 mRNA, enhances association of RNA helicase DHX9 with the IGF2 transcript, and promotes IGF2 transcription, creating a positive feedback loop between the intronic miRNA and its host gene.\",\n      \"method\": \"miRNA screen in Wilms' tumors; nuclear fractionation; RNA pulldown; DHX9 co-immunoprecipitation; miR-483-5p overexpression with IGF2 reporter and tumorigenesis assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (nuclear fractionation, RNA pulldown, Co-IP, in vivo tumorigenesis) in a single study\",\n      \"pmids\": [\"24298054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CpG methylation of the H19 ICR directly controls insulator function: insertion of a methylated ICR fragment into an episomal H19 minigene propagates the methylation mark, eliminates nuclease-hypersensitive sites characteristic of the maternal allele (indicating loss of CTCF-associated chromatin), and strongly attenuates insulator activity blocking maternal Igf2 expression.\",\n      \"method\": \"Episomal transfection with methylated/unmethylated ICR fragments; bisulfite sequencing; DNase I hypersensitivity assay; insulator functional assay in Hep3B cells\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (methylation propagation, chromatin structure, insulator function) in a single rigorous study\",\n      \"pmids\": [\"11509237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Most known enhancers for Igf2 in mesodermal tissues are located 3' of H19; a radiation-induced inversion (minute mutation) whose breakpoint disrupts an enhancer 3' of H19 causes drastic downregulation of Igf2 in all mesodermal tissues and placenta on paternal transmission, and maternal transmission of the inversion leads to methylation of the H19 DMR and biallelic Igf2 expression in endodermal tissues.\",\n      \"method\": \"Characterization of radiation-induced chromosomal inversion; RT-PCR expression analysis; bisulfite methylation analysis; genetic crosses with parent-of-origin tracking\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — natural genetic mutant with defined molecular lesion and multiple tissue-specific phenotypic readouts\",\n      \"pmids\": [\"11923202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Monoallelic expression at the Igf2/H19 locus occurs by at least two distinct mechanisms: developmentally regulated silencing of the paternal H19 promoter, and transcriptional insulation of the maternal Igf2 promoters; both are ultimately dependent on a common cis-acting element upstream of H19; additional Igf2 expression is independent of the shared enhancer.\",\n      \"method\": \"In vivo enhancer deletion (homologous recombination); ectopic H19 DMR transgenic analysis; allele-specific expression assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic deletion plus transgenic analysis with allele-specific readouts\",\n      \"pmids\": [\"11689707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IGF2 produced and secreted by adult β-cells functions as an autocrine activator of the β-cell IGF-1 receptor signaling pathway; β-cell-specific Igf2 knockout mice show reduced glucose-stimulated insulin secretion in aging and under high-fat diet, reduced β-cell mass expansion during pregnancy, and blunted β-cell mass adaptation to acute insulin resistance.\",\n      \"method\": \"β-cell-specific conditional Igf2 knockout mice; glucose tolerance tests; GSIS measurements; β-cell mass morphometry; pregnancy and high-fat diet metabolic challenges\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple defined physiological phenotypic readouts across multiple metabolic contexts\",\n      \"pmids\": [\"26384384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hippocampal IGF2 is expressed predominantly in pericytes; learning significantly increases pericytic Igf2 expression in the hippocampus in a neuronal activity-dependent manner; pericyte-specific (but not fibroblast- or neuron-specific) Igf2 knockout impairs long-term memory and blunts learning-induced neuronal immediate early gene (Arc, Egr1, c-Fos) protein upregulation.\",\n      \"method\": \"Cell-type-specific Igf2 knockout in pericytes, fibroblasts, and neurons using Cre lines; behavioral memory testing; neuronal IEG protein quantification; single-cell expression analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with behavioral and molecular phenotypic readouts across multiple cell types as controls\",\n      \"pmids\": [\"37788670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hippocampal CIM6P/IGF2R is necessary for memory consolidation but dispensable for learning, memory retrieval, and reconsolidation; it controls training-induced upregulation of de novo protein synthesis (including Arc, Egr1, c-Fos proteins) without affecting their mRNA induction; systemic or hippocampal mannose-6-phosphate (the IGF2R ligand) enhances memory in a CIM6P/IGF2R-dependent manner.\",\n      \"method\": \"CIM6P/IGF2R pharmacological inhibition in rats; neuron-specific knockdown in mice; protein synthesis assays; mRNA vs. protein quantification; mannose-6-phosphate injection behavioral experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological + genetic KD with multiple orthogonal mechanistic and behavioral readouts\",\n      \"pmids\": [\"32369018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IGF-II activates ERK1/2, PI3K/Akt/mTOR/p70S6K, and focal adhesion kinase signaling pathways in extravillous trophoblasts, promoting cell migration and invasion; endostatin specifically inhibits IGF-II-induced activation of these kinases and blocks IGF-II-stimulated trophoblast invasion without affecting proliferation; Akt1 isoform knockdown reveals that endostatin-mediated inhibition of Akt is critically Akt1-dependent.\",\n      \"method\": \"Transwell migration/invasion assays; Western blot for phospho-Akt, phospho-ERK1/2, phospho-p70S6K, phospho-FAK; viral shRNA knockdown of Akt1 in SGHPL-5 cells; villous explant cultures\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling readouts, genetic knockdown, and functional invasion assays in primary and cell line models\",\n      \"pmids\": [\"21933871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Igf2 deletion specifically in placental endocrine cells impairs placental hormone production (including prolactins), disrupts pregnancy-related maternal insulin resistance, and restricts nutrient partitioning to the fetus, causing fetal growth restriction and hypoglycemia; mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis in a placental endocrine cell-type-dependent manner.\",\n      \"method\": \"Conditional Igf2 knockout in placental endocrine cells; placental hormone profiling; maternal glucose and insulin measurements; fetal weight and blood glucose assays; protein synthesis assays; energy homeostasis measurements\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple mechanistic readouts (hormonal, metabolic, protein synthesis) replicated across cell types\",\n      \"pmids\": [\"37437545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The circadian regulators Per1 and Per2 are required for myoblast differentiation and muscle regeneration by activating Igf2 transcription as an autocrine promoter of differentiation; Per1/Per2 are recruited to the Igf2 promoter and enhancer, induce dynamic histone modifications, and facilitate promoter-enhancer interaction; depletion of Per1 or Per2 suppresses Igf2 activation and impairs myoblast differentiation.\",\n      \"method\": \"Per1/Per2 siRNA knockdown; ChIP for RNA Pol II and histone marks at Igf2 promoter/enhancer; 3C for promoter-enhancer interaction; in vitro differentiation assays; in vivo muscle regeneration; timed injury experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, 3C, genetic knockdown, and in vivo regeneration assays providing mechanistic pathway placement\",\n      \"pmids\": [\"34009269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IGF-II activates the IGF-1 receptor (IGF1R) and insulin receptor isoform A (IR-A), and downstream MAP kinase, PI3K, and G-protein-coupled signaling pathways to mediate cellular proliferation, survival, differentiation, and migration.\",\n      \"method\": \"Review synthesizing receptor binding, signaling pathway activation studies, and downstream effector analyses (cited primary studies)\",\n      \"journal\": \"Growth factors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review article synthesizing primary data; mechanism established across multiple studies but this paper itself is a review\",\n      \"pmids\": [\"22136428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mature IGF-II (71% of plasma IGF-II) and 'big' IGF-II activate IR-A and IR-B similarly, while pro-IGF-II activates IR significantly less; downstream Akt activation by mature and big IGF-II is greater in IR-A-expressing cells, consistent with higher IR-A affinity for IGF-II.\",\n      \"method\": \"IGF-II isoform quantification in human plasma; IR-A and IR-B signaling assays in IGF-IR-deficient cells expressing defined IR isoforms; Western blot for Akt phosphorylation\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cell system with IR isoform-specific readouts, single lab\",\n      \"pmids\": [\"21285309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IGF2 activates the PI3K/Akt/GSK3β pathway and the TGFβ pathway in chondrocytes; IGF2-driven proteoglycan gene transcription (Aggrecan, Versican) is mediated specifically by the PI3K pathway (blocked by LY294002), while IGF2-induced TGFβ mRNA upregulation is PI3K-independent.\",\n      \"method\": \"Microarray mRNA expression analysis; Western blot for phospho-Akt, phospho-GSK3β; PI3K inhibitor LY294002; quantitative RT-PCR for proteoglycan genes\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological pathway dissection with molecular readouts; single lab\",\n      \"pmids\": [\"18675921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"An IGF2 enhancer within the IGF2 gene locus controls chromatin looping to the nearby tyrosine hydroxylase (TH) gene promoter; hypomethylation of this IGF2 enhancer in major psychosis neurons is associated with increased TH protein levels; in mice, Igf2 enhancer deletion disrupts TH protein levels and striatal dopamine.\",\n      \"method\": \"Multi-omics approach: DNA methylation profiling, transcriptomics, chromatin conformation analysis in prefrontal cortex neurons (55 cases, 27 controls); Igf2 enhancer deletion in mice; dopamine and TH protein measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — chromatin conformation, enhancer deletion in mice, protein and metabolite measurements with human and mouse convergent data\",\n      \"pmids\": [\"31053723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DNA demethylation at the H19 imprinting control region (ICR) by 5-AzaCdR in choriocarcinoma cells reduces IGF2 and increases H19 expression, increases CTCF and cohesin recruitment to the ICR, alters histone modifications, and changes chromatin looping topology such that a CTCF site downstream of H19 enhancers switches association from the IGF2 promoter-proximal CTCF site to the ICR.\",\n      \"method\": \"5-AzaCdR treatment; bisulfite sequencing; ChIP for CTCF and cohesin; chromatin conformation capture (3C/4C); DNase I accessibility; RT-PCR\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal epigenomic and chromosome topology methods in a single study\",\n      \"pmids\": [\"23585276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Increased allelic Igf2 expression (biallelic vs. monoallelic vs. null) in the Apc(Min/+) intestinal adenoma mouse model elongates intestinal crypts, increases adenoma growth, and increases nuclear β-catenin staining; a soluble form of the full-length IGF2R (acting as an IGF-II ligand trap) rescues these Igf2-dependent intestinal and adenoma phenotypes, demonstrating IGF-II ligand bioavailability as the critical functional parameter.\",\n      \"method\": \"Genetic cross of Igf2 allelic dosage series with Apc(Min/+); sIGF2R transgene (ligand trap) rescue; intestinal crypt morphometry; adenoma counting; β-catenin immunostaining\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — allelic dosage series plus ligand-trap rescue provides clean epistasis; multiple readouts\",\n      \"pmids\": [\"16488992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of Igf2 paternal allele causes developmental lethality in p53 homozygous null mice; conditional deletion of Igf2 attenuates rapid tumor onset from homozygous p53 deletion; biallelic Igf2 expression accelerates carcinoma and sarcoma formation in p53+/- females with reductions in p53 LOH and apoptosis, establishing Igf2 pathway dependency of the p53 null phenotype.\",\n      \"method\": \"Genetic epistasis: Igf2 paternal null x p53 null crosses; conditional Igf2(fl/fl) x p53(fl/fl) deletion; tumor incidence and histology; apoptosis assays; LOH analysis\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis across multiple p53/Igf2 allele combinations with defined phenotypic readouts\",\n      \"pmids\": [\"22674894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Paternal Igf2 is expressed in adult hematopoietic stem cells (HSCs); Igf2 deficiency prevents age-related attrition of the HSC pool and is necessary for tissue homeostasis and regeneration, with Igf2 expression level critical for balancing HSC self-renewal and differentiation.\",\n      \"method\": \"Igf2 null mouse HSC analysis; flow cytometry of HSC pool; transplantation assays; bone marrow regeneration experiments; aging cohort comparisons\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined HSC phenotypic readouts; single lab, moderate evidence\",\n      \"pmids\": [\"28007480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The human IGF2 gene has at least two promoters with developmentally regulated usage: fetal organs predominantly use a promoter different from the adult liver promoter; steady-state IGF2 transcript levels are dramatically reduced in adult compared to fetal organs through a second level of transcriptional control independent of promoter switching; an alternative splice variant with altered coding potential is expressed at a constant low ratio in all fetal and adult organs.\",\n      \"method\": \"Northern blot analysis; S1 nuclease protection; alternative splicing analysis across fetal and adult tissue panels\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — foundational characterization using multiple tissues and methods; single lab\",\n      \"pmids\": [\"3503697\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2 is a paternally imprinted, maternally silenced growth factor whose monoallelic expression is controlled by allele-specific DNA methylation at the H19/IGF2 imprinting control region (ICR): on the maternal allele, unmethylated CTCF-binding sites recruit CTCF to form an enhancer-blocking insulator that prevents shared 3'-H19 enhancers from activating IGF2; on the paternal allele, ICR methylation abolishes CTCF binding, collapses the insulator, and permits enhancer-driven IGF2 transcription. IGF2 translation of its major 6.0-kb mRNA is additionally controlled post-transcriptionally by the p70S6K pathway, and transcription is activated by Egr-1 under hypoxia and by mTOR/PI3K-Akt signaling during myogenesis. The secreted IGF-II peptide activates IGF1R and IR-A receptors, engaging PI3K/Akt, ERK/MAPK, GSK3, and FAK signaling to drive proliferation, survival, differentiation, and migration in a broad range of cell types; it is sequestered and degraded via IGF2R (CIM6P receptor), which also plays an independent role in memory consolidation by controlling protein synthesis rates. In the brain, learning-induced pericyte-derived IGF2 acts on neurons via IGF2R to enable long-term memory formation, and hippocampal IGF2 enhances synaptic plasticity through GSK3β and AMPA receptor upregulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1978,\n      \"finding\": \"IGF-II (IGF2) was identified as a 67-amino acid single-chain polypeptide (sharing sequence homology with insulin and IGF-I) that accounts for the majority of insulin-like activity remaining in serum after insulin depletion, establishing its primary structure.\",\n      \"method\": \"Protein purification and primary structure determination\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original primary structure determination, foundational and replicated\",\n      \"pmids\": [\"658418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"IGF2 is encoded as a 180-amino acid preproprotein (preproIGF-II) containing a C-terminal E-peptide propeptide of 89 amino acids; the gene organization is related to the insulin gene family.\",\n      \"method\": \"cDNA cloning and sequencing of human IGF2 from adult liver mRNA\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cDNA cloning with direct sequence determination, replicated\",\n      \"pmids\": [\"6382021\", \"6382022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Human IGF2 is transcribed from at least two promoters with developmentally regulated usage; fetal tissues predominantly use a distinct promoter compared to adult liver, and steady-state IGF2 transcript levels are dramatically reduced in adult compared to fetal organs, indicating a second level of transcriptional control independent of promoter usage.\",\n      \"method\": \"Northern blot analysis and transcript characterization in fetal and adult human tissues\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple tissue types examined, developmental regulation documented\",\n      \"pmids\": [\"3503697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"IGF2 is monoallelically expressed (from the paternal allele) in normal human tissues; 69% of Wilms' tumors show biallelic (loss of imprinting) expression of IGF2, establishing loss of imprinting as an epigenetic mutational mechanism in cancer.\",\n      \"method\": \"Allele-specific RT-PCR using exonic polymorphisms in human tumor and normal tissues\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — allele-specific expression assay in large tumor cohort, highly replicated across labs\",\n      \"pmids\": [\"8385745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Excess IGF-II acts locally to increase cell number (DNA content) at sites of transgene expression (skin, alimentary canal, uterus) and has systemic effects on adult body weight, demonstrating distinct local and systemic growth-promoting actions of IGF-II in vivo.\",\n      \"method\": \"Keratin promoter-driven Igf2 transgenic mice; tissue DNA content and organ weight measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple transgenic lines, in vivo functional phenotype\",\n      \"pmids\": [\"7524092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IGF2 and H19 share common endoderm-specific enhancers located 3' of H19; paternal inheritance of an enhancer deletion abolishes Igf2 expression in endodermal tissues, and mice inheriting the deletion paternally are ~80% of normal size, demonstrating that IGF-II acts systemically to affect prenatal growth.\",\n      \"method\": \"Targeted deletion of enhancers by homologous recombination; allele-specific expression analysis; growth measurement\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — precise genetic deletion in ES cells, in vivo phenotype in multiple tissues, replicated\",\n      \"pmids\": [\"7544754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The major 6.0-kb IGF2 mRNA is stored untranslated in a 100S ribonucleoprotein particle in quiescent cells and is selectively mobilized and translated in exponentially growing cells; translational activation is blocked by rapamycin and mimicked by anisomycin, implicating the p70S6K/85S6K kinase signaling pathway in post-transcriptional regulation of IGF2.\",\n      \"method\": \"Sucrose gradient sedimentation, rapamycin/anisomycin pharmacological inhibition, polysome profiling in dispersed cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, pharmacological dissection of signaling pathway\",\n      \"pmids\": [\"7566093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IGF-II reduces programmed cell death (apoptosis) in skeletal muscle myoblasts both in vivo and in vitro, demonstrating a survival/anti-apoptotic function for IGF-II in muscle.\",\n      \"method\": \"Primary mdx and C57Bl muscle cell cultures; in vivo mouse models; apoptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — both in vitro and in vivo evidence with functional readout\",\n      \"pmids\": [\"17180029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Hypoxia induces IGF2 transcription from the P3 promoter in HepG2 cells through enhanced DNA-binding activity and increased expression of the transcription factor Egr-1; deletion of Egr-1 binding sites in the IGF2 P3 promoter abolishes hypoxic induction, and WT1 (a repressor) is simultaneously downregulated.\",\n      \"method\": \"Luciferase reporter assays, EMSA/supershift, RT-PCR, Western blot, Egr-1 cotransfection and promoter deletion analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted transcriptional activation with promoter deletion and co-transfection, multiple orthogonal methods\",\n      \"pmids\": [\"10606246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A CTCF-binding element upstream of H19 acts as an enhancer-blocking insulator controlling imprinted Igf2 expression; methylation of CpGs within CTCF-binding sites abolishes CTCF binding in vitro, and deletion of these sites eliminates enhancer-blocking activity in vivo, allowing biallelic Igf2 expression. Insulator activity is restricted to the maternal allele by paternal allele DNA methylation.\",\n      \"method\": \"In vitro CTCF binding assays with methylated/unmethylated substrates; deletion mutant transfection enhancer-blocking assays; allele-specific expression\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding assay plus in vivo functional deletion, multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"10839546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CpG methylation of the H19 imprinting control region (ICR) attenuates its CTCF-dependent insulator function; methylated ICR propagates stably in episomes, lacks nuclease hypersensitive sites, and fails to block enhancer-promoter communication, providing experimental support that methylation controls insulator activity.\",\n      \"method\": \"Episomal methylation propagation, nuclease sensitivity assay, insulator function assay in transfected Hep3B cells\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct functional test with methylated versus unmethylated substrates, multiple assays\",\n      \"pmids\": [\"11509237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Most known enhancers for Igf2 are located 3' of H19; a radiation-induced inversion (minute mutation) whose breakpoint disrupts a mesodermal enhancer downstream of H19 causes drastic downregulation of Igf2 in all mesodermal tissues and placenta upon paternal transmission, establishing the positions of mesodermal and extra-embryonic enhancers for Igf2.\",\n      \"method\": \"Genetic characterization of radiation-induced inversion; allele-specific expression analysis; maternal transmission effects on H19 DMR methylation\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic mapping of regulatory elements, multiple tissue analysis\",\n      \"pmids\": [\"11923202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"mTOR and amino acid sufficiency regulate IGF-II transcription through IGF2 promoter 3 and a downstream enhancer during C2C12 myoblast differentiation; mTOR's function in initiating differentiation targets IGF production (not IGF signaling), and this is independent of mTOR kinase activity but mediated by the PI3K-Akt pathway.\",\n      \"method\": \"Promoter-reporter assays, mTOR inhibition (rapamycin), PI3K-Akt pathway dissection, C2C12 myoblast differentiation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and genetic dissections, in vitro functional readouts\",\n      \"pmids\": [\"14662739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The oncogenic transcription factor PLAG1 is amplified and overexpressed in hepatoblastoma and transactivates IGF2 from the embryonic P3 promoter, providing a mechanism for IGF2 upregulation in this tumor type.\",\n      \"method\": \"Luciferase reporter assay (PLAG1 transactivation of IGF2 P3), real-time RT-PCR, comparative genomic hybridization\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assay establishing transactivation, replicated in multiple hepatoblastoma cell lines\",\n      \"pmids\": [\"14695992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CTCF mediates interchromosomal colocalization between the Igf2/H19 imprinting control region on chromosome 7 and Wsb1/Nf1 on chromosome 11; omission of CTCF or deletion of the maternal ICR abrogates this association and alters Wsb1/Nf1 gene expression, demonstrating CTCF-mediated long-range interchromosomal gene regulation.\",\n      \"method\": \"Modified chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — 3C and FISH with functional validation via CTCF omission and ICR deletion\",\n      \"pmids\": [\"16614224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Increased Igf2 allelic dosage (biallelic expression via H19 maternal allele disruption) in Apc(Min/+) mice elongates intestinal crypts and increases adenoma growth independently of systemic growth; a soluble form of IGF-II/mannose-6-phosphate receptor (sIGF2R) acting as an IGF-II ligand trap rescues this phenotype, demonstrating functional potency of IGF2 epigenetic dosage in intestinal cancer.\",\n      \"method\": \"Mouse genetic crosses (Igf2 null, biallelic, monoallelic), sIGF2R transgene expression, intestinal crypt and adenoma measurements, nuclear beta-catenin staining\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple allelic dosage conditions tested in vivo, rescued by ligand-specific trap\",\n      \"pmids\": [\"16488992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of IGF2R domains 11-12-13/IGF-II complex reveal that IGF-II Phe19 and Leu53 lock into a hydrophobic pocket unique to domain 11 of mammalian IGF2R; domain 13 modulates binding site flexibility. Mutagenesis confirms this 'binding hotspot' and shows that IGFBP and IGF2R have converged on the same high-affinity IGF-II binding site.\",\n      \"method\": \"X-ray crystallography (crystal structures of IGF2R domains 11-12, 11-12-13-14, and 11-12-13/IGF-II complex), site-directed mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation, high-resolution mechanistic detail\",\n      \"pmids\": [\"18046459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IGF2 activates PI3K/Akt and TGFβ signaling pathways in chondrocytes; PI3K-selective inhibitor LY294002 blocks Akt/GSK3β phosphorylation and abolishes IGF2-driven transcriptional upregulation of proteoglycans (Aggrecan and Versican), but does not suppress IGF2-induced TGFβ upregulation, indicating two independent signaling arms.\",\n      \"method\": \"Microarray gene expression analysis, Western blot (Akt, GSK3β phosphorylation), PI3K inhibitor (LY294002) experiments in C28/I2 chondrocyte cells\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection with two pathway readouts, in vitro chondrocyte model\",\n      \"pmids\": [\"18675921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cohesin is required for CTCF-mediated higher-order chromatin conformation at the IGF2-H19 locus; RNAi-mediated cohesin depletion disrupts allele-specific chromatin looping and coincides with changes in IGF2 expression; this conformation exists in both G1 and G2 phases, independent of cohesin's sister chromatid cohesion function.\",\n      \"method\": \"Chromosome conformation capture (3C), RNAi cohesin depletion, cell-cycle phase analysis, allele-specific expression\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — 3C with RNAi knockdown and expression readout, cell-cycle independence demonstrated\",\n      \"pmids\": [\"19956766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In rats, IGF-II enhances memory retention and prevents forgetting when injected into the hippocampus; learning-induced hippocampal IGF-II expression requires the transcription factor C/EBPβ and is essential for memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, ARC function, and GSK3; it correlates with GSK3β activation and increased GluR1/GRIA1 AMPA receptor subunit expression. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent persistent LTP after weak stimulation.\",\n      \"method\": \"Intrahippocampal recombinant IGF-II injection, inhibitory avoidance learning, receptor antagonists, protein synthesis inhibitors, hippocampal slice LTP, Western blot\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and behavioral methods, both in vivo and ex vivo validation\",\n      \"pmids\": [\"21270887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Endostatin inhibits IGF-II-induced migration and invasion of extravillous trophoblasts but not proliferation; endostatin interferes with IGF-II-activated downstream signaling kinases ERK1/2, Akt/mTOR/p70S6K, and focal adhesion kinase. Akt1-specific silencing demonstrates that endostatin-mediated inhibition of IGF-II-induced Akt phosphorylation is critically dependent on Akt1 isoform expression.\",\n      \"method\": \"Transwell migration/invasion assays, villous explant cultures, kinase Western blots, Akt1 shRNA silencing in SGHPL-5 trophoblast cells\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific knockdown with functional and signaling readouts\",\n      \"pmids\": [\"21933871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Autocrine IGF2/IGF1R signaling in cancer-associated fibroblasts (CAFs) induces myofibroblast differentiation (α-SMA expression and gel contractility); paracrine IGF2 from CAFs activates pro-survival AKT signaling in colorectal cancer cells via IGF1R/insulin receptor axis; IGF2-mediated physical matrix remodeling by CAFs (not secreted factors) facilitates tumor cell invasion in organotypic co-cultures.\",\n      \"method\": \"CAF co-culture, IGF2 knockdown, AKT signaling Western blot, floating collagen gel contractility, organotypic invasion assay, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary in vitro and in vivo assays with genetic knockdown and functional rescue\",\n      \"pmids\": [\"28534511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Akt1 and Igf2 null mutations independently decrease placental weight, fetal weight, and viability in mice; disruption of Igf2 does not affect AKT expression or activation, suggesting IGF2 acts upstream through additional effectors; Igf2 loss has more severe impact on prenatal survival and postnatal growth than Akt1 loss, with IGF2 contributing more to post-weaning growth.\",\n      \"method\": \"Genetic null mouse models (Akt1-/- and Igf2-/-) on CD1 background; placental, fetal, and postnatal growth phenotyping; AKT Western blot\",\n      \"journal\": \"The International journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — side-by-side genetic comparison on matched background with multiple phenotypic readouts\",\n      \"pmids\": [\"22562201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of p53 function creates Igf2 pathway dependency in vivo: developmental lethality occurs in p53 null mice lacking the paternal Igf2 allele; conditional Igf2 deletion attenuates rapid tumor onset in p53 null mice; biallelic Igf2 expression accelerates carcinoma/sarcoma formation in p53+/- females with reductions in p53 LOH and apoptosis.\",\n      \"method\": \"Conditional and germline Igf2/p53 double mutant mouse models; tumor incidence; gene expression profiling; apoptosis assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic combinations in vivo, epistasis established by compound mutants\",\n      \"pmids\": [\"22674894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"An intronic miRNA, miR-483-5p, embedded within IGF2 acts in a positive feedback loop by binding the 5'UTR of fetal IGF2 mRNA in the nucleus, enhancing the association of RNA helicase DHX9 with the IGF2 transcript, and promoting IGF2 transcription from fetal promoters; miR-483-5p is specifically overexpressed in Wilms' tumors and its ectopic expression increases tumorigenesis in IGF2-dependent sarcoma cells in vivo.\",\n      \"method\": \"miRNA screen in Wilms' tumors, nuclear miRNA pulldown, DHX9 co-association assay, promoter-specific transcription assays, in vivo tumorigenesis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — nuclear miRNA-mRNA interaction established with multiple orthogonal methods, in vivo functional validation\",\n      \"pmids\": [\"24298054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"5-Aza-2'deoxycytidine-induced demethylation of the H19 ICR in choriocarcinoma cells increases CTCF and cohesin recruitment, alters histone modifications, and reshapes chromatin looping such that a CTCF site downstream of H19 enhancers switches its association from the CTCF site upstream of IGF2 promoters to the ICR; a stable chromatin looping domain containing IGF2, marked by H3K27me3, forms independently of DNA methylation.\",\n      \"method\": \"5-AzaCdR treatment, CTCF/cohesin ChIP, histone modification ChIP, chromosome conformation capture (3C), allele-specific expression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple chromatin assays showing mechanistic link between methylation and topology\",\n      \"pmids\": [\"23585276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"β-cell-specific inactivation of Igf2 in mice (βIGF2KO) reveals that autocrine IGF2 regulates adult β-cell mass and function: βIGF2KO mice show reduced glucose-stimulated insulin secretion in aged females, impaired β-cell mass expansion during pregnancy and acute insulin resistance, and blunted β-cell proliferation, demonstrating that IGF2 produced and secreted by β-cells autocrinally activates IGF-1 receptor signaling.\",\n      \"method\": \"β-cell conditional Igf2 knockout mice; GSIS assays; glucose tolerance tests; β-cell mass morphometry; pregnancy and high-fat diet challenges\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout with multiple physiological challenges and functional readouts\",\n      \"pmids\": [\"26384384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IGF2 protein functions are mediated through IGF-1R and the insulin receptor isoform A (IR-A); IGF-2 activates Akt phosphorylation and GSK3β phosphorylation, induces β-catenin levels, and protects ALS patient-derived motor neurons from degeneration; AAV9-delivered IGF-2 to muscles of SOD1(G93A) ALS mice extended lifespan by 10% while preserving motor neurons and inducing motor axon regeneration.\",\n      \"method\": \"IGF-2 addition to patient motor neuron cultures, Akt/GSK3β Western blot, AAV9 muscle delivery in SOD1(G93A) mice, motor neuron counting, neuromuscular junction analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro signaling combined with in vivo gene delivery with functional phenotypic readouts\",\n      \"pmids\": [\"27180807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NF-κB activated by HER2/HER3 signaling targets IGF2 as a key downstream effector to promote tumor sphere formation in breast cancer; IGF2-PI3K signaling induces expression of the stemness transcription factor ID1, which in turn drives further IGF2 expression, forming a positive feedback loop (IGF2-ID1-IGF2 circuit) maintaining breast cancer stem-like cells; anti-IGF1/2 antibodies block tumorigenesis from IGF1Rhigh CSC populations in patient-derived xenografts.\",\n      \"method\": \"ID1 knockdown, IGF2 knockdown, NF-κB inhibition, anti-IGF1/2 antibody treatment, tumor sphere formation assay, patient-derived xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdowns and antibody blockade with functional rescue, in vivo xenograft validation\",\n      \"pmids\": [\"27546618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Paternal Igf2 is specifically expressed in adult hematopoietic stem cells (HSCs); Igf2 deficiency prevents age-related attrition of the HSC pool and is necessary for tissue homeostasis and regeneration, indicating that Igf2 expression level is critical to maintain the balance between HSC self-renewal and differentiation.\",\n      \"method\": \"Igf2 null adult mouse analysis; HSC pool quantification by flow cytometry; transplantation assays; in situ expression analysis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with quantitative HSC phenotyping and functional transplantation assays\",\n      \"pmids\": [\"28007480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hypomethylation of an enhancer within the IGF2 gene in prefrontal cortex neurons of schizophrenia and bipolar disorder patients is associated with increased tyrosine hydroxylase (TH) protein levels; chromatin conformation analysis shows this IGF2 enhancer contacts the TH gene promoter; mouse Igf2 enhancer deletion disrupts TH protein levels, striatal dopamine, and neuronal transcriptomic/proteomic organization.\",\n      \"method\": \"Neuron-specific DNA methylation profiling, chromatin conformation capture, proteomics, mouse Igf2 enhancer deletion, TH Western blot, dopamine measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics convergence plus mouse enhancer deletion with molecular and neurochemical phenotypes\",\n      \"pmids\": [\"31053723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hippocampal CIM6P/IGF2R (cation-independent mannose-6-phosphate/IGF2 receptor) is necessary for memory consolidation but not learning, retrieval, or reconsolidation; CIM6P/IGF2R controls training-induced upregulation of de novo protein synthesis (Arc, Egr1, c-Fos) without affecting their mRNA induction; hippocampal or systemic mannose-6-phosphate administration enhances memory in a CIM6P/IGF2R-dependent manner.\",\n      \"method\": \"CIM6P/IGF2R pharmacological inhibition in rats, neuron-specific Cre knockdown in mice, protein synthesis measurement, Western blot for IEG proteins vs. mRNA, behavioral memory assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic inhibition converge on same phenotype with mechanistic protein synthesis readout\",\n      \"pmids\": [\"32369018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IGF-II acts through both IGF-1R and insulin receptor isoform A (IR-A); mature and 'big' IGF-II exhibit similar activation of IR-A and IR-B signaling, while pro-IGF-II exhibits significantly less activation; downstream Akt activation by mature and 'big' IGF-II is greater in IR-A than IR-B cells, consistent with greater IR-A affinity for IGF-II.\",\n      \"method\": \"IGF-II isoform fractionation from human plasma, signaling assays in IGF-IR-deficient cells expressing IR-A or IR-B, Akt Western blot\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isotype-specific receptor cell lines with quantitative signaling readouts\",\n      \"pmids\": [\"21285309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Circadian master regulators Per1 and Per2 are required for proper myoblast differentiation and muscle regeneration; Per1 and Per2 activate Igf2 transcription by recruiting RNA polymerase II, enabling dynamic histone modifications, and establishing promoter-enhancer interactions at the Igf2 locus; muscle regeneration is faster when initiated at night when Per1, Per2, and Igf2 are maximally expressed.\",\n      \"method\": \"Per1/Per2 knockdown in myoblasts, in vivo muscle regeneration, ChIP for RNA Pol II and histone marks, chromatin conformation capture, circadian timing experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — chromatin-level mechanism validated in vitro and in vivo with circadian timing confirmation\",\n      \"pmids\": [\"34009269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hepatocyte-specific Igf2 deletion in SRSF3 knockout mice completely prevents hepatic fibrosis, inflammation, and tumor formation; in vitro, IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage, indicating that IGF2 overexpression promotes genomic instability and drives liver cancer.\",\n      \"method\": \"Double conditional knockout mice (Igf2/Srsf3); tumor incidence; DNA damage markers (γH2AX); DNA repair enzyme expression; IGF2 treatment of hepatoma cells in vitro\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double genetic deletion in vivo plus in vitro mechanistic confirmation with DNA damage readouts\",\n      \"pmids\": [\"35615981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hippocampal IGF2 is most highly expressed in pericytes; learning significantly increases pericytic Igf2 expression in the hippocampus in a neuronal activity-dependent manner; pericyte-specific (but not fibroblast- or neuron-specific) Igf2 knockout impairs long-term memory and blunts learning-dependent neuronal immediate early gene (IEG) induction, establishing a neuronal activity → pericyte IGF2 → neuron signaling axis required for long-term memory.\",\n      \"method\": \"Cell-type specific Igf2 knockout (pericyte, fibroblast, neuron), single-cell RNA-seq, activity-dependent expression measurement, behavioral memory tests, neuronal IEG Western blot\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific genetic knockouts with behavioral and molecular readouts, multiple controls\",\n      \"pmids\": [\"37788670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Igf2 deletion in placental endocrine cells impairs placental endocrine signaling (including prolactin production) to the mother, reduces pregnancy-related insulin resistance, and restricts fetal growth and causes fetal hypoglycemia; Igf2 controls protein synthesis and cellular energy homeostasis in placental endocrine cells in a cell-type-dependent manner, and has long-lasting effects on offspring metabolism in adulthood.\",\n      \"method\": \"Placental endocrine cell-specific Igf2 knockout mice; placental hormone (prolactin) measurement; maternal insulin resistance testing; fetal growth and glucose measurement; protein synthesis and energy metabolism assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional endocrine cell-specific deletion with multiple mechanistic and physiological readouts in vivo\",\n      \"pmids\": [\"37437545\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IGF2 encodes a 67-amino acid secreted growth factor (processed from a 180-aa preproprotein) that signals primarily through IGF-1R and insulin receptor isoform A (IR-A) to activate PI3K/Akt, GSK3β, and MAPK pathways; its imprinted paternal-only expression is maintained by allele-specific DNA methylation that controls CTCF/cohesin-dependent chromatin insulation and enhancer access at the H19-IGF2 locus; its translation is regulated post-transcriptionally by mTOR/p70S6K; it acts as an autocrine/paracrine mitogen in fetal growth, β-cell mass adaptation, muscle regeneration (via Per1/Per2-dependent circadian epigenetic priming), and adult hematopoietic stem cell maintenance, and functions in the brain as a pericyte-derived, learning-induced signal required for long-term memory consolidation via CIM6P/IGF2R-dependent protein synthesis control.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IGF2 encodes a paternally expressed, maternally imprinted secreted growth factor whose monoallelic transcription is governed by allele-specific DNA methylation at the H19/IGF2 imprinting control region: on the maternal allele, unmethylated CTCF-binding sites recruit CTCF to establish an enhancer-blocking insulator that prevents shared downstream enhancers from activating IGF2, whereas paternal-allele methylation abolishes CTCF binding and permits enhancer-driven transcription [PMID:10839546, PMID:7544754, PMID:11509237]. Beyond imprinting, IGF2 transcription is activated by Egr-1 under hypoxia, by mTOR/PI3K-Akt signaling during myogenesis, by the circadian regulators Per1/Per2, and by a positive-feedback loop involving its intronic miR-483-5p and the RNA helicase DHX9, while its major mRNA undergoes growth-dependent translational control via the p70S6K pathway [PMID:10606246, PMID:14662739, PMID:34009269, PMID:24298054, PMID:7566093]. The secreted IGF-II peptide signals through IGF1R and insulin receptor isoform A to engage PI3K/Akt, ERK/MAPK, GSK3β, and FAK cascades that drive proliferation, survival, migration, and differentiation in tissues including trophoblasts, chondrocytes, β-cells, and hematopoietic stem cells, and is sequestered by IGF2R, which also independently regulates protein synthesis rates [PMID:21933871, PMID:26384384, PMID:18675921, PMID:32369018]. In the hippocampus, learning induces pericyte-derived IGF2, which acts through IGF2R-dependent GSK3β activation and AMPA receptor upregulation to consolidate long-term memory [PMID:21270887, PMID:37788670].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Before the regulatory architecture of IGF2 was understood, this study established that IGF2 uses multiple developmentally regulated promoters with dramatic postnatal transcriptional downregulation, framing the gene as a fetal growth factor with complex transcriptional control.\",\n      \"evidence\": \"Northern blot, S1 nuclease protection, and splice-variant analysis across human fetal and adult tissue panels\",\n      \"pmids\": [\"3503697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter-specific regulatory factors not identified\", \"Imprinting not yet discovered for this locus\", \"Single lab, limited quantification methods\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Two foundational questions were resolved simultaneously: that IGF2 and H19 compete for shared downstream enhancers to achieve reciprocal imprinted expression, and that IGF2 mRNA translation is independently regulated through a p70S6K-dependent pathway that mobilizes stored mRNP particles.\",\n      \"evidence\": \"Targeted enhancer deletion in ES cells with tissue-specific expression analysis; polysome fractionation with rapamycin/anisomycin pharmacology and metabolic labeling\",\n      \"pmids\": [\"7544754\", \"7566093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The insulator mechanism separating maternal from paternal allele access to enhancers was not yet identified\", \"Identity of trans-acting factors controlling mRNP storage unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The question of how IGF2 transcription responds to microenvironmental stress was answered: hypoxia activates IGF2 via the P3 promoter through Egr-1 binding, establishing IGF2 as a hypoxia-responsive gene with defined cis-elements.\",\n      \"evidence\": \"P3 promoter deletion/luciferase reporters, EMSA/supershift for Egr-1, cotransfection epistasis in HepG2 cells\",\n      \"pmids\": [\"10606246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Egr-1-driven IGF2 activation operates in vivo under physiological hypoxia not shown\", \"Other stress-responsive transcription factors at P3 not surveyed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The central epigenetic switch for IGF2 imprinting was identified: methylation of CpG sites within CTCF-binding sites at the ICR abolishes CTCF binding and insulator activity, directly linking allele-specific DNA methylation to monoallelic IGF2 expression.\",\n      \"evidence\": \"In vitro CTCF binding assays with methylated/unmethylated oligonucleotides; CTCF-site deletion in vivo; transgenic mouse models\",\n      \"pmids\": [\"10839546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ICR methylation is established and maintained through development not addressed\", \"Three-dimensional chromatin topology consequences not yet mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The insulator model was mechanistically solidified by showing that methylated ICR fragments propagate their methylation state, eliminate nuclease-hypersensitive sites, and attenuate insulator function, while genetic dissection confirmed dual mechanisms—promoter silencing and transcriptional insulation—at the locus.\",\n      \"evidence\": \"Episomal methylation-propagation assay, DNase I hypersensitivity, insulator functional assay; in vivo enhancer/DMR deletion with allele-specific expression\",\n      \"pmids\": [\"11509237\", \"11689707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cohesin involvement not yet recognized\", \"Whether additional cis-regulatory elements contribute beyond the ICR not fully resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"A natural chromosomal inversion disrupting enhancers 3′ of H19 demonstrated that most mesodermal IGF2 enhancers lie downstream of H19, and that enhancer disruption on the maternal chromosome paradoxically causes ICR methylation and biallelic IGF2 expression in endoderm, revealing tissue-specific regulatory interdependencies.\",\n      \"evidence\": \"Characterization of radiation-induced minute inversion; RT-PCR and bisulfite methylation across tissues; parent-of-origin crosses\",\n      \"pmids\": [\"11923202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which enhancer loss triggers ICR methylation change on maternal allele unclear\", \"Enhancer identity at single-element resolution not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The question of how differentiation signals converge on IGF2 was answered for myogenesis: mTOR activates IGF2 transcription from the P3 promoter independent of its kinase activity, with PI3K-Akt acting upstream, positioning IGF2 as an autocrine differentiation signal downstream of nutrient-sensing pathways.\",\n      \"evidence\": \"Rapamycin treatment, kinase-dead mTOR constructs, IGF2 P3 promoter-luciferase reporters, C2C12 differentiation assays\",\n      \"pmids\": [\"14662739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intermediary transcription factors between mTOR and P3 promoter not identified\", \"Whether this pathway operates in non-muscle differentiation contexts untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Two advances expanded the functional scope of the IGF2 locus: CTCF at the ICR mediates interchromosomal associations that regulate genes in trans, and IGF2 dosage was shown to drive intestinal adenoma growth in an Apc-mutant model, with soluble IGF2R rescuing the phenotype by sequestering IGF-II ligand.\",\n      \"evidence\": \"3C and FISH for interchromosomal contacts with CTCF knockdown; Igf2 allelic dosage series crossed with Apc(Min/+), soluble IGF2R transgene rescue\",\n      \"pmids\": [\"16614224\", \"16488992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of trans-chromosomal associations on IGF2 expression itself not quantified\", \"Whether sIGF2R-based therapeutic strategy is broadly applicable beyond intestinal tumors unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The structural basis for IGF-II clearance was resolved: crystal structures of IGF2R domains 11–13 with IGF-II revealed that domain 11 contacts IGF-II through a hydrophobic pocket engaging Phe19 and Leu53, with domain 13 modulating flexibility, defining the molecular determinants of ligand sequestration.\",\n      \"evidence\": \"X-ray crystallography of IGF2R/IGF-II complex; site-directed mutagenesis of binding residues\",\n      \"pmids\": [\"18046459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IGF2R-mediated internalization and lysosomal routing of IGF-II proceed structurally not addressed\", \"Whether therapeutic disruption of this interface is feasible not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Multiple studies converged to define IGF-II's downstream signaling and a new biological role: IGF-II activates IGF1R/IR-A engaging PI3K/Akt, ERK, and FAK to promote trophoblast invasion; mature and 'big' IGF-II preferentially signal through IR-A; and hippocampal IGF-II was shown to be essential for memory consolidation through IGF2R, GSK3β, and GluR1 AMPA receptor upregulation.\",\n      \"evidence\": \"Trophoblast migration/invasion assays with phospho-kinase readouts and Akt1 knockdown; IR isoform-specific signaling in IGF1R-null cells; intrahippocampal IGF-II injection with pharmacological blockade and LTP recordings\",\n      \"pmids\": [\"21933871\", \"21285309\", \"21270887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the neuronal IGF2R signaling intermediates linking receptor to GSK3β not fully delineated\", \"Whether IR-A vs. IGF1R preferential activation is context-dependent in vivo not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic epistasis between Igf2 and p53 established that Igf2 is required for the developmental and tumorigenic consequences of p53 loss: Igf2 deletion causes lethality in p53-null embryos and attenuates tumorigenesis, while biallelic Igf2 accelerates carcinoma/sarcoma formation with reduced p53 LOH.\",\n      \"evidence\": \"Igf2 paternal null × p53 null crosses; conditional double deletion; tumor histology, apoptosis, and LOH analysis\",\n      \"pmids\": [\"22674894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which IGF2 pathway compensates for p53 loss not defined\", \"Whether this epistasis generalizes to human tumors not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two layers of IGF2 locus regulation were uncovered: chromatin conformation capture showed that DNA demethylation restructures CTCF/cohesin-mediated chromatin loops at the ICR to switch enhancer access, and the intronic miR-483-5p was found to form a nuclear pool that recruits DHX9 to IGF2 mRNA and enhances IGF2 transcription, creating a positive feedback loop.\",\n      \"evidence\": \"5-AzaCdR demethylation with 3C/4C, ChIP for CTCF and cohesin, bisulfite sequencing; nuclear fractionation, RNA pulldown, DHX9 Co-IP, miR-483-5p overexpression with tumorigenesis assays\",\n      \"pmids\": [\"23585276\", \"24298054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-483-5p feedback loop operates in normal development or only in tumor contexts unclear\", \"How cohesin is recruited to unmethylated ICR independently of CTCF not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The autocrine function of IGF2 in adult β-cells was established: β-cell-specific Igf2 knockout impairs glucose-stimulated insulin secretion during aging and metabolic stress, and reduces β-cell mass expansion during pregnancy, defining IGF2 as a critical autocrine regulator of β-cell adaptation.\",\n      \"evidence\": \"β-cell-specific conditional Igf2 knockout mice; glucose tolerance, GSIS, β-cell morphometry under aging, high-fat diet, and pregnancy\",\n      \"pmids\": [\"26384384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which receptor mediates autocrine IGF2 signaling in β-cells not conclusively determined\", \"Downstream transcriptional targets of autocrine IGF2 in β-cells not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A regulatory function of the IGF2 locus beyond IGF-II protein was revealed: an IGF2 enhancer controls chromatin looping to the tyrosine hydroxylase promoter in trans, and its hypomethylation in psychosis neurons correlates with increased TH protein and striatal dopamine, with enhancer deletion in mice recapitulating altered TH levels.\",\n      \"evidence\": \"DNA methylation profiling, chromatin conformation analysis in human prefrontal cortex neurons; Igf2 enhancer deletion in mice with TH and dopamine measurements\",\n      \"pmids\": [\"31053723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGF2 enhancer-TH looping is a general regulatory principle or locus-specific not known\", \"Causal relationship between methylation change and psychosis not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The mechanism by which IGF2R supports memory was clarified: IGF2R controls training-induced de novo protein synthesis (not mRNA induction) and is required specifically for memory consolidation, not learning or retrieval, establishing IGF2R as a translational gatekeeper in hippocampal neurons.\",\n      \"evidence\": \"Pharmacological IGF2R inhibition and neuron-specific knockdown; protein synthesis assays; mRNA vs. protein dissociation; mannose-6-phosphate behavioral rescue\",\n      \"pmids\": [\"32369018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IGF2R engagement mechanistically couples to translational machinery not identified\", \"Whether IGF-II is the sole physiological IGF2R ligand relevant for this function not confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The circadian regulators Per1 and Per2 were identified as direct transcriptional activators of Igf2 in myoblasts: they are recruited to the Igf2 promoter and enhancer, induce histone modifications, and facilitate promoter-enhancer looping required for differentiation and muscle regeneration.\",\n      \"evidence\": \"Per1/Per2 siRNA knockdown; ChIP for Pol II and histone marks; 3C for promoter-enhancer interaction; in vivo muscle regeneration assays\",\n      \"pmids\": [\"34009269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Per1/Per2-Igf2 axis operates in non-muscle differentiation contexts unknown\", \"Clock-dependence of Per1/Per2 action at the Igf2 locus not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies resolved cell-type-specific IGF2 functions in vivo: hippocampal IGF2 critical for memory consolidation is pericyte-derived and neuronal-activity-dependent, while placental endocrine cell-derived IGF2 controls placental hormone production, maternal insulin resistance, and fetal nutrient partitioning through regulation of protein synthesis and energy homeostasis.\",\n      \"evidence\": \"Cell-type-specific Igf2 conditional KO in pericytes, neurons, and fibroblasts with behavioral and IEG readouts; conditional Igf2 KO in placental endocrine cells with hormone, metabolic, and protein synthesis measurements\",\n      \"pmids\": [\"37788670\", \"37437545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals linking neuronal activity to pericytic Igf2 induction not identified\", \"Whether placental IGF2 acts in autocrine vs. paracrine mode on neighboring endocrine cells not distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the identity of signaling intermediates between IGF2R and translational machinery in neurons; how ICR methylation patterns are initially established and maintained through development; whether the miR-483-5p/DHX9 positive-feedback loop on IGF2 operates in normal physiology; and the full receptor-specificity map (IGF1R vs. IR-A vs. IGF2R) for IGF-II actions across different tissue contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstitution of IGF2R-to-translation signaling pathway\", \"Developmental establishment of ICR methylation not mechanistically resolved in the available literature\", \"Tissue-specific receptor usage for IGF-II not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [5, 13, 16, 17, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 13, 16, 17, 19, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [16, 19, 20, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 17, 18, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 19, 20, 21]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 10, 23]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 8, 9, 18]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 14, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IGF1R\",\n      \"IGF2R\",\n      \"CTCF\",\n      \"INSR\",\n      \"DHX9\",\n      \"PER1\",\n      \"PER2\",\n      \"EGR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IGF2 encodes a paternally imprinted, secreted 67-amino-acid mitogenic peptide (processed from a 180-aa preproprotein) that signals through IGF-1R and insulin receptor isoform A (IR-A) to activate PI3K/Akt/GSK3β and MAPK pathways, functioning as an autocrine/paracrine growth factor in fetal development, placental endocrine signaling, β-cell mass regulation, muscle regeneration, and long-term memory consolidation [PMID:658418, PMID:6382021, PMID:26384384, PMID:37788670, PMID:37437545]. Monoallelic paternal expression is enforced by allele-specific DNA methylation of the H19 imprinting control region, which governs CTCF/cohesin-dependent chromatin insulation and enhancer access; loss of imprinting leading to biallelic expression drives overexpression in Wilms' tumor, intestinal adenoma, and other cancers [PMID:10839546, PMID:19956766, PMID:8385745, PMID:16488992]. IGF2 translation is post-transcriptionally regulated by the mTOR/p70S6K pathway, and its transcription is controlled by circadian regulators Per1/Per2, hypoxia-responsive Egr-1, and the oncogenic factor PLAG1 [PMID:7566093, PMID:34009269, PMID:10606246, PMID:14695992]. In the hippocampus, pericyte-derived IGF2 acts through CIM6P/IGF2R to promote de novo protein synthesis required for long-term memory consolidation [PMID:37788670, PMID:32369018, PMID:21270887].\",\n  \"teleology\": [\n    {\n      \"year\": 1978,\n      \"claim\": \"Establishing the primary identity of IGF-II as a distinct insulin-family peptide resolved the molecular basis of non-suppressible insulin-like activity in serum and enabled all subsequent functional studies.\",\n      \"evidence\": \"Protein purification and amino acid sequencing from human serum\",\n      \"pmids\": [\"658418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational processing pathway not yet elucidated\", \"Receptor identity unknown\", \"Genomic organization unknown\"]\n    },\n    {\n      \"year\": 1984,\n      \"claim\": \"cDNA cloning revealed IGF2 is synthesized as a 180-aa preproprotein with an 89-aa E-peptide, defining the precursor-to-mature processing step and linking IGF2 to the insulin gene family.\",\n      \"evidence\": \"cDNA cloning and sequencing from human adult liver mRNA\",\n      \"pmids\": [\"6382021\", \"6382022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proprotein convertase(s) responsible for E-peptide cleavage not identified\", \"Biological activity of E-peptide unknown\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrating monoallelic paternal expression of IGF2 in normal tissues and biallelic expression (loss of imprinting) in Wilms' tumors established epigenetic deregulation as a cancer mechanism, opening the imprinting field to oncology.\",\n      \"evidence\": \"Allele-specific RT-PCR using exonic polymorphisms in human tumor and normal tissue cohorts\",\n      \"pmids\": [\"8385745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism enforcing monoallelic silencing not yet identified\", \"Causality of LOI in tumorigenesis versus bystander effect unresolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Enhancer deletion and transgenic studies together established that IGF2 acts as both a local mitogen increasing cell number and a systemic growth factor controlling prenatal body size through shared enhancers 3′ of H19.\",\n      \"evidence\": \"Targeted enhancer deletion by homologous recombination in mice; keratin-driven Igf2 transgenic mice with tissue DNA content and growth measurements\",\n      \"pmids\": [\"7524092\", \"7544754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of tissue-specific enhancers beyond endoderm not mapped\", \"Relative contributions of IGF-1R versus other receptors in fetal growth unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery that IGF2 mRNA is stored in untranslated 100S ribonucleoprotein particles and mobilized via the mTOR/p70S6K pathway revealed a post-transcriptional control layer linking nutrient sensing to IGF2 protein output.\",\n      \"evidence\": \"Sucrose gradient sedimentation, rapamycin/anisomycin pharmacological inhibition, polysome profiling\",\n      \"pmids\": [\"7566093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding proteins composing the 100S particle not identified\", \"Cis-regulatory elements in IGF2 mRNA mediating translational repression unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of the CTCF-dependent enhancer-blocking insulator at the H19 ICR, silenced on the paternal allele by CpG methylation, provided the mechanistic basis for allele-specific IGF2 expression and linked DNA methylation directly to chromatin insulator function.\",\n      \"evidence\": \"In vitro CTCF binding assays with methylated/unmethylated DNA; in vivo deletion of CTCF sites; episomal methylation propagation and insulator assays\",\n      \"pmids\": [\"10839546\", \"11509237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How methylation is established and maintained at the paternal ICR during development not fully resolved\", \"Contribution of individual CTCF sites versus cluster not dissected\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Biallelic IGF2 expression in Apc(Min/+) mice accelerated intestinal adenoma growth and was rescued by a soluble IGF2R ligand trap, directly establishing IGF2 epigenetic dosage as a functional driver in intestinal tumorigenesis.\",\n      \"evidence\": \"Allelic dosage genetic crosses with Apc(Min/+); sIGF2R transgene rescue; intestinal crypt and adenoma measurements\",\n      \"pmids\": [\"16488992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGF2 acts on tumor cells, stroma, or both in this context not resolved\", \"Therapeutic window for IGF2R-based ligand trapping not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Crystal structures of IGF2R domains 11-13 in complex with IGF-II revealed the hydrophobic binding pocket (Phe19, Leu53) for clearance/signaling via the mannose-6-phosphate receptor, showing convergent evolution with IGFBPs on the same IGF-II surface.\",\n      \"evidence\": \"X-ray crystallography of IGF2R domain complexes with site-directed mutagenesis validation\",\n      \"pmids\": [\"18046459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length IGF2R structure and mechanism of IGF-II internalization/degradation not resolved\", \"How domain 13 flexibility modulates affinity in vivo unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Cohesin was shown to be required for CTCF-mediated chromatin looping at the IGF2-H19 locus independently of its cohesion function, establishing the architectural co-dependence of CTCF and cohesin in imprinting control.\",\n      \"evidence\": \"3C and RNAi-mediated cohesin depletion with allele-specific expression readout, cell-cycle phase analysis\",\n      \"pmids\": [\"19956766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cohesin loading at the ICR requires CTCF directly or other factors not determined\", \"Impact of cohesin mutations on IGF2 imprinting in human disease not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Intrahippocampal IGF-II injection enhanced memory consolidation and promoted persistent LTP through IGF2R (not IGF-1R), GSK3β, and de novo protein synthesis, establishing a cognitive function for IGF2 beyond its classical growth role.\",\n      \"evidence\": \"Recombinant IGF-II hippocampal injection, inhibitory avoidance learning, receptor antagonists, protein synthesis inhibitors, hippocampal slice electrophysiology\",\n      \"pmids\": [\"21270887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of endogenous hippocampal IGF2 not identified at this point\", \"Downstream translational targets mediating memory enhancement not catalogued\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of a positive feedback loop in which the intronic miR-483-5p binds the 5′UTR of IGF2 mRNA in the nucleus and recruits RNA helicase DHX9 to enhance IGF2 transcription revealed an embedded cis-regulatory amplification circuit overexpressed in Wilms' tumor.\",\n      \"evidence\": \"Nuclear miRNA pulldown, DHX9 co-association assay, promoter-specific transcription assays, in vivo tumorigenesis in sarcoma model\",\n      \"pmids\": [\"24298054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-483-5p feedback operates in non-tumor tissues unknown\", \"Structural basis of 5′UTR recognition by miR-483-5p not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"β-cell-specific Igf2 knockout demonstrated that autocrine IGF2/IGF-1R signaling is required for adaptive β-cell mass expansion during pregnancy and insulin resistance, extending IGF2's role to metabolic adaptation in adults.\",\n      \"evidence\": \"Conditional β-cell Igf2 knockout mice with GSIS assays, glucose tolerance tests, β-cell morphometry under pregnancy and high-fat diet challenges\",\n      \"pmids\": [\"26384384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human β-cells maintain IGF2 expression to the same extent as mouse not established\", \"Downstream transcriptional program in β-cells not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Per1/Per2 were found to recruit RNA Pol II and enable promoter-enhancer looping at the Igf2 locus, linking circadian regulation to muscle regeneration timing and explaining why regeneration is faster at circadian peaks of Igf2 expression.\",\n      \"evidence\": \"Per1/Per2 knockdown in myoblasts, in vivo muscle regeneration, ChIP for Pol II and histone marks, 3C, circadian timing experiments\",\n      \"pmids\": [\"34009269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other clock genes participate in Igf2 regulation not tested\", \"Mechanism by which Per proteins recruit Pol II to Igf2 promoters not elucidated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cell-type-specific knockouts identified pericytes as the critical hippocampal source of learning-induced IGF2 that signals to neurons to promote IEG-dependent protein synthesis for long-term memory, completing a neurovascular signaling circuit (neuronal activity → pericyte IGF2 → neuron).\",\n      \"evidence\": \"Pericyte-, fibroblast-, and neuron-specific Igf2 knockout; scRNA-seq; behavioral memory tests; neuronal IEG protein measurement\",\n      \"pmids\": [\"37788670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor (IGF2R vs. IGF-1R) mediating pericyte-to-neuron signaling not definitively resolved in this context\", \"Mechanism of neuronal activity sensing by pericytes unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placental endocrine cell-specific Igf2 deletion revealed that IGF2 controls protein synthesis and energy homeostasis within the placenta and orchestrates maternal metabolic adaptation (insulin resistance, prolactin), establishing IGF2 as a master regulator of the feto-maternal metabolic dialogue.\",\n      \"evidence\": \"Placental endocrine cell-specific Igf2 knockout mice with placental hormone, maternal insulin resistance, fetal glucose, and protein synthesis measurements\",\n      \"pmids\": [\"37437545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGF2 acts via IGF-1R or IR-A in placental endocrine cells not resolved\", \"How placental IGF2 programs offspring adult metabolism remains mechanistically open\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of differential IGF2 signaling through IGF-1R versus IR-A, the identity of the translational repression complex sequestering IGF2 mRNA, how neuronal activity is communicated to pericytes to induce IGF2, and whether IGF2 LOI is sufficient to initiate (rather than accelerate) tumorigenesis independently of cooperating mutations.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No IGF2/IGF-1R co-crystal structure available\", \"RNA-binding proteins in the 100S storage particle unidentified\", \"Pericyte activity-sensing mechanism unknown\", \"Causality of LOI alone in tumor initiation not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4, 19, 26, 27, 35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 23, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 5, 26, 35, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [17, 19, 20, 27, 28, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 22, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 15, 23, 24, 28, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 19, 20, 27, 28, 32]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 26]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [19, 30, 31, 35]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 8, 9, 13, 24, 33]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 10, 14, 18, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IGF1R\",\n      \"INSR\",\n      \"IGF2R\",\n      \"CTCF\",\n      \"PER1\",\n      \"PER2\",\n      \"DHX9\",\n      \"PLAG1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}