{"gene":"CDH2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2015,"finding":"CDH2 (N-cadherin) stabilizes FGFR1 in mouse epiblast stem cells (mEpiSCs), contributing to FGF signaling-dependent self-renewal; co-immunoprecipitation revealed direct interaction between CDH2 and FGFR1, and CDH2 knockdown attenuated pluripotency-related gene expression while CDH1 overexpression could not rescue this effect.","method":"Co-immunoprecipitation, siRNA knockdown, western blot, stable transfection","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue experiments in single lab with two orthogonal methods","pmids":["26420260"],"is_preprint":false},{"year":2015,"finding":"Conditional knockout of Cdh2 specifically in Sertoli cells (but not germ cells) compromised blood-testis barrier function, delayed meiotic progression from prophase to metaphase I, increased germ cell apoptosis, and reduced sperm counts, establishing CDH2 as a functionally required component of basal ectoplasmic specializations at the blood-testis barrier.","method":"Conditional knockout (Cdh2 loxP × Amh-Cre mice), BTB integrity assay, histology, TUNEL assay","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with specific cellular phenotype, double-KO epistasis confirming cell-type specificity, replicated across multiple readouts","pmids":["25631347"],"is_preprint":false},{"year":2013,"finding":"Selective disruption of CDH2-based adherens junctions using peptides that interfere with the histidine-alanine-valine (HAV) extracellular homophilic interaction domain caused disruption of zonula adherens, abnormal intracellular accumulation of N-cadherin, massive apoptosis of ependymal cells, and denudation of brain ventricular walls, demonstrating that CDH2-mediated adherens junctions are required for ependymal cell survival.","method":"Peptide blocking of CDH2 HAV domain in vivo, immunostaining, TUNEL assay","journal":"Journal of neuropathology and experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional intervention with domain-specific peptide, single lab, multiple readouts","pmids":["23965744"],"is_preprint":false},{"year":2013,"finding":"Forced expression of Cdh2 in mouse iPSCs substantially enhanced neural differentiation efficiency, while shRNA-mediated knockdown of Cdh2 blocked neural differentiation, establishing Cdh2 as a critical regulator of neural differentiation in mouse induced pluripotent stem cells.","method":"Forced expression, shRNA knockdown, gene expression microarray, neural differentiation assays","journal":"Stem cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function experiments in same system, single lab","pmids":["23416351"],"is_preprint":false},{"year":2014,"finding":"Inactivation of CDH2 in the dorsal telencephalon disrupted adherens junctions between radial glial cells, dramatically increased progenitor cell proliferation, widely dispersed progenitor cells throughout the developing neocortex, and produced a double cortex-like (subcortical band heterotopia) phenotype, establishing CDH2 as required for normal progenitor proliferation control and cortical lamination.","method":"Conditional knockout, histology, immunostaining, BrdU proliferation assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific morphological and cellular phenotype, replicated with afadin co-inactivation establishing pathway context","pmids":["25100583"],"is_preprint":false},{"year":2018,"finding":"FOXF1 transcription factor directly binds to Cdh2 and Cdh11 promoters and differentially regulates their transcription; FOXF1 deletion promotes a switch from CDH2 (N-cadherin) to CDH11 (cadherin-11) in lung myofibroblasts, increasing invasion and collagen secretion; re-expression of CDH2 in FOXF1-deficient cells reduced myofibroblast invasion in vitro.","method":"ChIP (promoter binding), transgenic mouse FOXF1 conditional knockout, rescue overexpression, invasion assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct promoter ChIP, conditional KO mouse model, functional rescue with CDH2 re-expression, multiple orthogonal methods","pmids":["29642003"],"is_preprint":false},{"year":2019,"finding":"Cdh2 (N-cadherin) is required for Myosin-II-dependent internalisation of the zebrafish neural plate; abrogation of Cdh2 results in defective Myosin-II distribution, mislocalised internalisation events, and defective neural plate morphogenesis, placing CDH2 upstream of actomyosin contractility during neurulation.","method":"Quantitative live imaging, mutant analysis, Myosin-II inhibition, zebrafish genetics","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutant analysis with live imaging and functional readout, single lab","pmids":["30755665"],"is_preprint":false},{"year":2020,"finding":"Conditional removal of Cdh2 from postmitotic neuroblasts of the subpallium delayed interneuron precursor migration into the pallium and resulted in a cell-type-specific decrease in adult cortical interneuron numbers, with part of the precursors failing to enter the cortical plate and being eliminated postnatally; this was not due to decreased mitosis, elevated cell death in the subpallium, fate-switching, or altered target selection.","method":"Conditional knockout, immunohistochemistry, TUNEL assay, interneuron composition analysis","journal":"Cerebral cortex","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific phenotypic readout, multiple negative controls ruling out alternative mechanisms, single lab","pmids":["31402374"],"is_preprint":false},{"year":2022,"finding":"ALKBH5 (an m6A RNA demethylase) in Sertoli cells regulates m6A levels on Cdh2 mRNA; IGF2BP1/2/3 complexes and YTHDF1 promote Cdh2 mRNA translation; ALKBH5 knockout in mice severely disordered basal ectoplasmic specialization (in which N-cadherin is a main structural protein) and compromised blood-testis barrier integrity.","method":"m6A-seq, RNA immunoprecipitation-qPCR, co-immunoprecipitation, polysome fractionation-qPCR, western blot, Alkbh5-KO mouse model, transmission electron microscopy","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical methods (m6A-seq, RIP, polysome fractionation, Co-IP) plus in vivo KO with ultrastructural validation","pmids":["36418936"],"is_preprint":false},{"year":2021,"finding":"A missense mutation in CDH2 that affects N-cadherin maturation causes familial ADHD; CRISPR/Cas9 knock-in mice harboring the human mutation showed hyperactivity, impaired presynaptic vesicle clustering, attenuated evoked and spontaneous transmitter release, reduced tyrosine hydroxylase expression, and decreased dopamine levels in ventral midbrain and prefrontal cortex.","method":"CRISPR/Cas9 knock-in mouse, behavioral testing, electrophysiology (evoked/spontaneous transmitter release), immunostaining, dopamine quantification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knock-in mouse with human mutation, multiple orthogonal readouts (behavior, electrophysiology, biochemistry), methylphenidate rescue","pmids":["34702855"],"is_preprint":false},{"year":2023,"finding":"In mouse embryonic stem cells differentiating into presomitic mesoderm (PSM)-like tissue, Cdh2 knockout downregulated FGF signalling and caused premature cessation of Hes7 oscillations; conversely, Cdh2 overexpression upregulated FGF signalling and prolonged Hes7 oscillations. ChIP-seq established Cdh2 as a direct transcriptional target of Hes7. Cdh2 protein showed a posterior-high gradient in PSM despite dynamic mRNA expression, placing CDH2 downstream of Hes7 and upstream of FGF signalling in the segmentation clock.","method":"ChIP-seq (anti-Hes7), Cdh2 knockout in Hes7-reporter ESC-derived PSM, live imaging of Hes7 oscillations, Cdh2 overexpression","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-seq for direct target identification combined with KO and overexpression with live imaging readout in same system","pmids":["40951951"],"is_preprint":false},{"year":2019,"finding":"A homozygous CDH2 variant (p.Val289Ile) found in a hypopituitarism patient impaired cell aggregation in vitro; stably transfected L1 fibroblast lines expressing wild-type CDH2 formed large aggregates, whereas cells transfected with variant CDH2 or non-transfected cells showed impaired aggregation, demonstrating that this variant disrupts the cell-adhesion function of N-cadherin.","method":"Stable transfection of L1 fibroblasts, quantitative cell aggregation assay","journal":"Endocrine connections","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with variant vs. wild-type comparison, single lab, single method","pmids":["37166408"],"is_preprint":false},{"year":2019,"finding":"Endothelin-1 (EDN1) increases CDH2 expression in human mesenchymal stem cells through endothelin receptor A (EDNRA); promoter activity assays identified GATA2 and MZF1 as transcription factors that bind the CDH2 promoter and are required for EDN1-induced CDH2 upregulation; deletion or point mutation of GATA2 or MZF1 binding sequences abolished this promoter activity.","method":"CDH2 promoter activity assay, EDNRA blocker (BQ123), site-directed mutagenesis of promoter binding sites, western blot","journal":"Molecular therapy. Methods & clinical development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assay with mutagenesis identifies specific TF binding sites, pharmacological receptor blockade, single lab","pmids":["31194009"],"is_preprint":false},{"year":2024,"finding":"Nuclear translocation of the cleaved intracellular domain of PCDH9 interacts with DNMT1 and increases its activity, leading to increased DNA methylation at the CDH2 promoter and consequent downregulation of CDH2 expression, thereby reducing gastric cancer cell migration and in vivo metastasis.","method":"Co-immunoprecipitation (PCDH9 ICD–DNMT1), DNMT1 activity assay, bisulfite sequencing of CDH2 promoter, CDH2 expression rescue, in vivo metastasis model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus DNMT1 activity assay plus bisulfite sequencing plus functional rescue, single lab","pmids":["38357662"],"is_preprint":false},{"year":2023,"finding":"In TM4 Sertoli cells, the AP-1 transcription factor Junb directly binds to AP-1 regulatory elements in the proximal Cdh2 promoter region; ChIP-qPCR and luciferase reporter assays with site-directed mutagenesis confirmed that Junb recruits to several AP-1 sites and that knockdown of Junb decreases Cdh2 expression.","method":"siRNA knockdown, ChIP-qPCR, luciferase reporter assay with site-directed mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP-qPCR plus luciferase with mutagenesis confirms direct TF–promoter interaction, single lab","pmids":["37119763"],"is_preprint":false},{"year":2022,"finding":"lncRNA SNHG15 preferentially localizes at cellular protrusions directed by IMP1; SNHG15 forms a complex with nucleolin and co-transports it to cell protrusions, where nucleolin binds CDH2 mRNA, stabilizes it locally, and enhances its translation, thereby promoting breast cancer cell invasion.","method":"RNA immunoprecipitation, co-immunoprecipitation, proximity ligation, localization imaging, CDH2 mRNA stability and translation assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and Co-IP demonstrating complex, localization imaging, mRNA stability assay, single lab","pmids":["37958584"],"is_preprint":false},{"year":2021,"finding":"ARTEMIN promotes CDH2 expression via p44/42 MAP kinase signalling; siRNA depletion of CDH2 reduced ARTN-enhanced oncogenicity and chemoresistance to 5-FU, and forced CDH2 expression rescued the reduced mesenchymal properties after ARTN depletion, placing CDH2 downstream of ARTN/p44/42 MAPK in colorectal carcinoma.","method":"siRNA knockdown, forced expression, MAP kinase inhibition, cell invasion/migration assays, xenograft model","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via rescue experiment plus pharmacological inhibition, single lab, multiple functional readouts","pmids":["34422665"],"is_preprint":false},{"year":2022,"finding":"CRISPR/Cas9-mediated knockout of Cdh2 in 4T1 breast cancer cells confirmed absence of N-cadherin protein and significantly reduced tumor cell migration, establishing a direct role for CDH2 in cancer cell motility.","method":"CRISPR/Cas9 gene knockout, western blot confirmation, transwell migration assay","journal":"Pharmaceutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with protein confirmation and defined functional readout, single lab","pmids":["35890278"],"is_preprint":false},{"year":2025,"finding":"In osteoblast-like MC3T3 cells, N-cadherin (CDH2) binds to PI3K components p85α and p110, restraining PI3K-Akt-β-catenin signalling; Cdh2 ablation enhances Tgf-β1-activated PI3K signalling, increases Tgf-β1 production via enhanced Sp1/Lef-1 binding to the Tgfb1 promoter, upregulates miR-21, and decreases PTEN, creating a pro-tumorigenic feed-forward loop that promotes breast cancer cell growth.","method":"Cdh2 ablation, Co-immunoprecipitation (CDH2–p85α/p110), PI3K activity assay, Tgfb1 promoter assay with ChIP (Sp1/Lef-1), miR-21 measurement, PTEN western blot, co-culture and co-injection tumor models, Tgfbr1 genetic ablation epistasis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — Co-IP identifies CDH2–PI3K binding, multiple orthogonal methods, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.22.683948"],"is_preprint":true},{"year":2025,"finding":"Ndrg1b promotes recycling of N-cadherin (cdh2) to the plasma membrane in zebrafish muscle cells; loss of Ndrg1b disrupts N-cadherin subcellular localization, impairs cell adhesion in vitro, and causes defective skeletal muscle morphogenesis phenotypically similar to cdh2 loss, identifying Ndrg1b as a component of the endocytic trafficking machinery for CDH2.","method":"Zebrafish morpholino/genetic knockdown of ndrg1b, N-cadherin localization imaging, cell aggregation assay, rescue experiments","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization imaging and aggregation assay in model organism, preprint only, no direct biochemical reconstitution of trafficking","pmids":["bio_10.1101_2025.05.08.652902"],"is_preprint":true},{"year":2025,"finding":"In the DSG2 interactome of primary neonatal cardiomyocytes, over half of DSG2-associated proteins are shared with the N-cadherin (CDH2) interactome; plakoglobin (JUP) and plakophilin 2 (PKP2) were the most abundant proteins shared between DSG2 and CDH2 interactomes, suggesting CDH2 and DSG2 participate in overlapping adhesion complexes at the intercalated disc.","method":"Proximity labeling (BioID), quantitative mass spectrometry, interactome comparison","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling MS identifies interaction network but no direct binding validation for CDH2-specific partners; preprint","pmids":["bio_10.1101_2025.06.09.658637"],"is_preprint":true},{"year":2025,"finding":"In chick embryo dorsal forebrain neuroepithelium, Cdh2 spatiotemporal expression mirrors a tissue stiffness gradient during roof plate invagination; the interplay between Cdh2 and F-actin modulates tissue stiffness by regulating apical adherens junction stability and cortical F-actin distribution along the apico-basal axis, contributing to roof plate morphogenesis.","method":"Atomic force microscopy (tissue stiffness mapping), Cdh2 expression analysis, F-actin perturbation, adherens junction immunostaining in chick embryo","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — AFM stiffness mapping correlated with Cdh2 expression plus F-actin perturbation; preprint, no direct genetic ablation of Cdh2 reported in this study","pmids":["bio_10.1101_2025.11.03.686203"],"is_preprint":true},{"year":2025,"finding":"lncRNA MEG3 recruits the histone acetyltransferase EP300 to the CDH2 locus in hippocampal neurons of ASD rats, activating CDH2 transcription; CDH2 upregulation represses neuronal viability and promotes apoptosis in this model, and MEG3 knockdown ameliorated ASD-like learning/memory impairments through reduced CDH2.","method":"Microarray, ChIP (MEG3–EP300 recruitment to CDH2 promoter), CDH2 depletion, MEG3 knockdown in rat ASD model","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates EP300 recruitment to CDH2 promoter plus in vivo rescue experiments, single lab","pmids":["35697159"],"is_preprint":false}],"current_model":"CDH2 (N-cadherin) is a transmembrane Ca2+-dependent cell adhesion molecule that mediates homophilic cell-cell adhesion via its extracellular HAV domain, anchors cortical F-actin through adherens junction complexes containing plakoglobin and plakophilin-2, and transduces intracellular signals by binding to and restraining PI3K components (p85α/p110) to suppress Akt-β-catenin signalling; its transcription is regulated by Hes7 (segmentation clock), FOXF1, AP-1/Junb, MEG3/EP300, and DNMT1-mediated promoter methylation, while its mRNA translation is controlled by ALKBH5-dependent m6A modification read by IGF2BP1/2/3 and YTHDF1; functionally, CDH2 is required for blood-testis barrier integrity, cortical progenitor proliferation control, interneuron migration and survival, presynaptic vesicle clustering and dopaminergic neurotransmission, FGF-dependent segmentation clock oscillations, and myosin-II-mediated tissue internalisation."},"narrative":{"mechanistic_narrative":"CDH2 (N-cadherin) is a Ca2+-dependent homophilic cell-cell adhesion molecule whose extracellular HAV-domain-mediated interactions assemble adherens junctions required for tissue integrity and morphogenesis across multiple developmental contexts [PMID:23965744, PMID:37166408]. Its adhesive function underpins the blood-testis barrier, where Sertoli-cell-specific loss disrupts basal ectoplasmic specializations, delays meiosis, and reduces sperm output [PMID:25631347], and it controls cortical development by maintaining radial-glia adherens junctions that restrain progenitor proliferation and ensure proper lamination [PMID:25100583]. Beyond static adhesion, CDH2 couples to actomyosin contractility to drive tissue shape change, acting upstream of Myosin-II during neural plate internalisation [PMID:30755665]. In the segmentation clock, CDH2 is a direct transcriptional target of Hes7 and operates upstream of FGF signalling to sustain oscillations [PMID:40951951], and in stem cells it stabilizes FGFR1 to support FGF-dependent self-renewal [PMID:26420260] while promoting neural differentiation [PMID:23416351]. In neurons CDH2 organizes presynaptic vesicle clustering and dopaminergic neurotransmission, and a maturation-impairing missense mutation causes familial ADHD [PMID:34702855]. CDH2 also transduces intracellular signals by binding the PI3K subunits p85α and p110 to restrain Akt–β-catenin signalling [PMID:bio_10.1101_2025.10.22.683948]. Its expression is regulated transcriptionally by FOXF1 [PMID:29642003], AP-1/Junb [PMID:37119763], GATA2/MZF1 downstream of endothelin-1 [PMID:31194009], and MEG3/EP300 [PMID:35697159], and is silenced by DNMT1-mediated promoter methylation [PMID:38357662], while its mRNA translation is controlled by ALKBH5-dependent m6A modification read by IGF2BP1/2/3 and YTHDF1 [PMID:36418936].","teleology":[{"year":2013,"claim":"Established that CDH2-based adherens junctions, acting through the HAV homophilic interface, are required for epithelial cell survival rather than adhesion alone, and that CDH2 levels gate neural differentiation.","evidence":"HAV-domain blocking peptides in vivo with TUNEL readout; gain- and loss-of-function in mouse iPSCs with differentiation assays","pmids":["23965744","23416351"],"confidence":"Medium","gaps":["Mechanism linking junction disruption to apoptosis not defined","Downstream effectors of CDH2 in differentiation not identified"]},{"year":2014,"claim":"Showed CDH2 restrains progenitor proliferation and enforces cortical lamination by maintaining radial-glia adherens junctions, linking adhesion to proliferation control.","evidence":"Conditional knockout in dorsal telencephalon with BrdU proliferation and histology, plus afadin co-inactivation","pmids":["25100583"],"confidence":"High","gaps":["Signalling pathway coupling junction loss to hyperproliferation not resolved","How dispersed progenitors generate band heterotopia unclear"]},{"year":2015,"claim":"Defined CDH2 as a required structural component of the blood-testis barrier and as a stabilizer of FGFR1 supporting FGF-dependent stem-cell self-renewal, extending its role from adhesion to receptor regulation.","evidence":"Sertoli-cell conditional KO with BTB and meiosis readouts; reciprocal Co-IP and knockdown in mEpiSCs","pmids":["25631347","26420260"],"confidence":"High","gaps":["Structural basis of CDH2–FGFR1 interaction unknown","Whether FGFR1 stabilization underlies BTB or differentiation roles untested"]},{"year":2018,"claim":"Identified FOXF1 as a direct transcriptional regulator that controls a CDH2-to-CDH11 cadherin switch governing myofibroblast invasion, establishing transcriptional control of CDH2 with functional consequences.","evidence":"Promoter ChIP, FOXF1 conditional KO mouse, CDH2 re-expression rescue, invasion assay","pmids":["29642003"],"confidence":"High","gaps":["How cadherin identity dictates invasive phenotype mechanistically unclear"]},{"year":2019,"claim":"Expanded the regulatory landscape of CDH2 transcription and showed that point variants disrupt adhesion function, linking CDH2 to morphogenesis and disease.","evidence":"Promoter assays with mutagenesis identifying GATA2/MZF1 downstream of EDN1/EDNRA; L1 fibroblast aggregation assay of the p.Val289Ile hypopituitarism variant; zebrafish Myosin-II internalisation analysis","pmids":["31194009","37166408","30755665"],"confidence":"Medium","gaps":["Whether adhesion defect alone explains hypopituitarism not established","Molecular link between CDH2 and Myosin-II distribution undefined"]},{"year":2021,"claim":"Provided causal genetic evidence that a CDH2 maturation-impairing mutation causes ADHD via defective presynaptic vesicle clustering and dopaminergic deficits, defining a synaptic function for CDH2.","evidence":"CRISPR/Cas9 knock-in mouse with behavior, electrophysiology, dopamine quantification and methylphenidate rescue; ARTN/p44-42 MAPK epistasis in colorectal cancer","pmids":["34702855","34422665"],"confidence":"High","gaps":["How impaired maturation produces vesicle-clustering defect not resolved","Connection between adhesion and dopaminergic signalling unclear"]},{"year":2022,"claim":"Established post-transcriptional control of CDH2 through m6A modification and demonstrated a direct requirement for CDH2 in cancer cell motility.","evidence":"m6A-seq, RIP-qPCR, polysome fractionation and Alkbh5-KO mouse with ultrastructure; CRISPR KO in 4T1 cells with migration assay","pmids":["36418936","35890278"],"confidence":"High","gaps":["Whether translational and adhesive roles of CDH2 are separable in cancer untested","Site-specific m6A residues on Cdh2 mRNA not mapped"]},{"year":2023,"claim":"Positioned CDH2 within the segmentation clock as a direct Hes7 target acting upstream of FGF signalling, and identified AP-1/Junb as a direct promoter activator.","evidence":"Hes7 ChIP-seq, Cdh2 KO/overexpression in ESC-derived PSM with live Hes7 oscillation imaging; ChIP-qPCR and luciferase mutagenesis for Junb","pmids":["40951951","37119763"],"confidence":"High","gaps":["How CDH2 feeds back to modulate FGF signalling mechanistically unknown","Relationship between CDH2 protein gradient and oscillatory output unresolved"]},{"year":2024,"claim":"Showed epigenetic silencing of CDH2 via PCDH9-ICD-stimulated DNMT1 promoter methylation suppresses gastric cancer metastasis, adding a methylation-based regulatory layer.","evidence":"Co-IP, DNMT1 activity assay, bisulfite sequencing of CDH2 promoter, rescue and in vivo metastasis model","pmids":["38357662"],"confidence":"Medium","gaps":["Whether CDH2 loss is necessary versus correlative for metastasis suppression unclear"]},{"year":2025,"claim":"Proposed a signalling output for CDH2 in which it binds PI3K subunits to restrain Akt-β-catenin signalling, and implicated trafficking and adhesion-complex partners, extending CDH2 beyond junctional adhesion.","evidence":"Co-IP of CDH2 with p85α/p110, PI3K and promoter assays in osteoblast-like cells (preprint); zebrafish Ndrg1b recycling study (preprint); DSG2/CDH2 interactome by BioID-MS identifying JUP and PKP2 (preprint)","pmids":["bio_10.1101_2025.10.22.683948","bio_10.1101_2025.05.08.652902","bio_10.1101_2025.06.09.658637"],"confidence":"Low","gaps":["PI3K-restraint model from a single preprint without independent confirmation","Trafficking and intercalated-disc partner claims lack direct CDH2 binding validation"]},{"year":null,"claim":"How CDH2's adhesive, mechanotransductive, receptor-stabilizing, and signalling functions are integrated within a single tissue context remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model unifying CDH2 binding to FGFR1, PI3K, and junctional partners","Whether intracellular signalling roles are conserved beyond bone/cancer cells untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,19]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,21]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,10]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,10]}],"complexes":["adherens junction"],"partners":["FGFR1","PIK3R1","PIK3CA","JUP","PKP2","DSG2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19022","full_name":"Cadherin-2","aliases":["CDw325","Neural cadherin","N-cadherin"],"length_aa":906,"mass_kda":99.8,"function":"Calcium-dependent cell adhesion protein; preferentially mediates homotypic cell-cell adhesion by dimerization with a CDH2 chain from another cell. Cadherins may thus contribute to the sorting of heterogeneous cell types. Acts as a regulator of neural stem cells quiescence by mediating anchorage of neural stem cells to ependymocytes in the adult subependymal zone: upon cleavage by MMP24, CDH2-mediated anchorage is affected, leading to modulate neural stem cell quiescence. Plays a role in cell-to-cell junction formation between pancreatic beta cells and neural crest stem (NCS) cells, promoting the formation of processes by NCS cells (By similarity). Required for proper neurite branching. Required for pre- and postsynaptic organization (By similarity). CDH2 may be involved in neuronal recognition mechanism. In hippocampal neurons, may regulate dendritic spine density. May promote axon outgrowth and motor fiber repair via DSP-mediated recruitment to outgrowth tips (By similarity)","subcellular_location":"Cell membrane; Cell membrane, sarcolemma; Cell junction; Cell surface; Cell junction, desmosome; Cell junction, adherens junction; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/P19022/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDH2","classification":"Not Classified","n_dependent_lines":112,"n_total_lines":1208,"dependency_fraction":0.09271523178807947},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000170558","cell_line_id":"CID000875","localizations":[{"compartment":"cell_contact","grade":3},{"compartment":"membrane","grade":3}],"interactors":[{"gene":"CTNNA1","stoichiometry":10.0},{"gene":"CTNNB1","stoichiometry":10.0},{"gene":"BPNT1","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"ARVCF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000875","total_profiled":1310},"omim":[{"mim_id":"621377","title":"HAREL-TORA NEURODEVELOPMENTAL SYNDROME; HATONS","url":"https://www.omim.org/entry/621377"},{"mim_id":"620993","title":"CHD2-ADJACENT SUPPRESSIVE REGULATORY RNA; CHASERR","url":"https://www.omim.org/entry/620993"},{"mim_id":"619957","title":"ATTENTION DEFICIT-HYPERACTIVITY DISORDER 8; ADHD8","url":"https://www.omim.org/entry/619957"},{"mim_id":"619858","title":"AUTOINFLAMMATORY-PANCYTOPENIA SYNDROME; AIPCS","url":"https://www.omim.org/entry/619858"},{"mim_id":"619309","title":"PROTEIN PHOSPHATASE, MAGNESIUM/MANGANESE-DEPENDENT, 1F; PPM1F","url":"https://www.omim.org/entry/619309"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":183.5}],"url":"https://www.proteinatlas.org/search/CDH2"},"hgnc":{"alias_symbol":["CDHN","CD325"],"prev_symbol":["NCAD"]},"alphafold":{"accession":"P19022","domains":[{"cath_id":"2.60.40.60","chopping":"39-122","consensus_level":"high","plddt":83.1254,"start":39,"end":122},{"cath_id":"2.60.40.60","chopping":"165-257","consensus_level":"high","plddt":91.179,"start":165,"end":257},{"cath_id":"2.60.40.60","chopping":"265-372","consensus_level":"medium","plddt":95.5421,"start":265,"end":372},{"cath_id":"2.60.40.60","chopping":"380-488","consensus_level":"medium","plddt":94.1291,"start":380,"end":488},{"cath_id":"2.60.40.60","chopping":"495-595","consensus_level":"high","plddt":93.1604,"start":495,"end":595},{"cath_id":"2.60.40.60","chopping":"603-700","consensus_level":"high","plddt":88.8532,"start":603,"end":700}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19022","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19022-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19022-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDH2","jax_strain_url":"https://www.jax.org/strain/search?query=CDH2"},"sequence":{"accession":"P19022","fasta_url":"https://rest.uniprot.org/uniprotkb/P19022.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19022/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19022"}},"corpus_meta":[{"pmid":"25771201","id":"PMC_25771201","title":"CDH2 and CDH11 act as regulators of stem cell fate decisions.","date":"2015","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25771201","citation_count":134,"is_preprint":false},{"pmid":"28280076","id":"PMC_28280076","title":"Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy.","date":"2017","source":"Circulation. 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cardiomyocytes","date":"2025-06-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.09.658637","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37130,"output_tokens":6022,"usd":0.10086,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14701,"output_tokens":3814,"usd":0.084428,"stage2_stop_reason":"end_turn"},"total_usd":0.185288,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"CDH2 (N-cadherin) stabilizes FGFR1 in mouse epiblast stem cells (mEpiSCs), contributing to FGF signaling-dependent self-renewal; co-immunoprecipitation revealed direct interaction between CDH2 and FGFR1, and CDH2 knockdown attenuated pluripotency-related gene expression while CDH1 overexpression could not rescue this effect.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blot, stable transfection\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue experiments in single lab with two orthogonal methods\",\n      \"pmids\": [\"26420260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Conditional knockout of Cdh2 specifically in Sertoli cells (but not germ cells) compromised blood-testis barrier function, delayed meiotic progression from prophase to metaphase I, increased germ cell apoptosis, and reduced sperm counts, establishing CDH2 as a functionally required component of basal ectoplasmic specializations at the blood-testis barrier.\",\n      \"method\": \"Conditional knockout (Cdh2 loxP × Amh-Cre mice), BTB integrity assay, histology, TUNEL assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with specific cellular phenotype, double-KO epistasis confirming cell-type specificity, replicated across multiple readouts\",\n      \"pmids\": [\"25631347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Selective disruption of CDH2-based adherens junctions using peptides that interfere with the histidine-alanine-valine (HAV) extracellular homophilic interaction domain caused disruption of zonula adherens, abnormal intracellular accumulation of N-cadherin, massive apoptosis of ependymal cells, and denudation of brain ventricular walls, demonstrating that CDH2-mediated adherens junctions are required for ependymal cell survival.\",\n      \"method\": \"Peptide blocking of CDH2 HAV domain in vivo, immunostaining, TUNEL assay\",\n      \"journal\": \"Journal of neuropathology and experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional intervention with domain-specific peptide, single lab, multiple readouts\",\n      \"pmids\": [\"23965744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Forced expression of Cdh2 in mouse iPSCs substantially enhanced neural differentiation efficiency, while shRNA-mediated knockdown of Cdh2 blocked neural differentiation, establishing Cdh2 as a critical regulator of neural differentiation in mouse induced pluripotent stem cells.\",\n      \"method\": \"Forced expression, shRNA knockdown, gene expression microarray, neural differentiation assays\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function experiments in same system, single lab\",\n      \"pmids\": [\"23416351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Inactivation of CDH2 in the dorsal telencephalon disrupted adherens junctions between radial glial cells, dramatically increased progenitor cell proliferation, widely dispersed progenitor cells throughout the developing neocortex, and produced a double cortex-like (subcortical band heterotopia) phenotype, establishing CDH2 as required for normal progenitor proliferation control and cortical lamination.\",\n      \"method\": \"Conditional knockout, histology, immunostaining, BrdU proliferation assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific morphological and cellular phenotype, replicated with afadin co-inactivation establishing pathway context\",\n      \"pmids\": [\"25100583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXF1 transcription factor directly binds to Cdh2 and Cdh11 promoters and differentially regulates their transcription; FOXF1 deletion promotes a switch from CDH2 (N-cadherin) to CDH11 (cadherin-11) in lung myofibroblasts, increasing invasion and collagen secretion; re-expression of CDH2 in FOXF1-deficient cells reduced myofibroblast invasion in vitro.\",\n      \"method\": \"ChIP (promoter binding), transgenic mouse FOXF1 conditional knockout, rescue overexpression, invasion assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct promoter ChIP, conditional KO mouse model, functional rescue with CDH2 re-expression, multiple orthogonal methods\",\n      \"pmids\": [\"29642003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cdh2 (N-cadherin) is required for Myosin-II-dependent internalisation of the zebrafish neural plate; abrogation of Cdh2 results in defective Myosin-II distribution, mislocalised internalisation events, and defective neural plate morphogenesis, placing CDH2 upstream of actomyosin contractility during neurulation.\",\n      \"method\": \"Quantitative live imaging, mutant analysis, Myosin-II inhibition, zebrafish genetics\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutant analysis with live imaging and functional readout, single lab\",\n      \"pmids\": [\"30755665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional removal of Cdh2 from postmitotic neuroblasts of the subpallium delayed interneuron precursor migration into the pallium and resulted in a cell-type-specific decrease in adult cortical interneuron numbers, with part of the precursors failing to enter the cortical plate and being eliminated postnatally; this was not due to decreased mitosis, elevated cell death in the subpallium, fate-switching, or altered target selection.\",\n      \"method\": \"Conditional knockout, immunohistochemistry, TUNEL assay, interneuron composition analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific phenotypic readout, multiple negative controls ruling out alternative mechanisms, single lab\",\n      \"pmids\": [\"31402374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALKBH5 (an m6A RNA demethylase) in Sertoli cells regulates m6A levels on Cdh2 mRNA; IGF2BP1/2/3 complexes and YTHDF1 promote Cdh2 mRNA translation; ALKBH5 knockout in mice severely disordered basal ectoplasmic specialization (in which N-cadherin is a main structural protein) and compromised blood-testis barrier integrity.\",\n      \"method\": \"m6A-seq, RNA immunoprecipitation-qPCR, co-immunoprecipitation, polysome fractionation-qPCR, western blot, Alkbh5-KO mouse model, transmission electron microscopy\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical methods (m6A-seq, RIP, polysome fractionation, Co-IP) plus in vivo KO with ultrastructural validation\",\n      \"pmids\": [\"36418936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A missense mutation in CDH2 that affects N-cadherin maturation causes familial ADHD; CRISPR/Cas9 knock-in mice harboring the human mutation showed hyperactivity, impaired presynaptic vesicle clustering, attenuated evoked and spontaneous transmitter release, reduced tyrosine hydroxylase expression, and decreased dopamine levels in ventral midbrain and prefrontal cortex.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse, behavioral testing, electrophysiology (evoked/spontaneous transmitter release), immunostaining, dopamine quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knock-in mouse with human mutation, multiple orthogonal readouts (behavior, electrophysiology, biochemistry), methylphenidate rescue\",\n      \"pmids\": [\"34702855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In mouse embryonic stem cells differentiating into presomitic mesoderm (PSM)-like tissue, Cdh2 knockout downregulated FGF signalling and caused premature cessation of Hes7 oscillations; conversely, Cdh2 overexpression upregulated FGF signalling and prolonged Hes7 oscillations. ChIP-seq established Cdh2 as a direct transcriptional target of Hes7. Cdh2 protein showed a posterior-high gradient in PSM despite dynamic mRNA expression, placing CDH2 downstream of Hes7 and upstream of FGF signalling in the segmentation clock.\",\n      \"method\": \"ChIP-seq (anti-Hes7), Cdh2 knockout in Hes7-reporter ESC-derived PSM, live imaging of Hes7 oscillations, Cdh2 overexpression\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-seq for direct target identification combined with KO and overexpression with live imaging readout in same system\",\n      \"pmids\": [\"40951951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous CDH2 variant (p.Val289Ile) found in a hypopituitarism patient impaired cell aggregation in vitro; stably transfected L1 fibroblast lines expressing wild-type CDH2 formed large aggregates, whereas cells transfected with variant CDH2 or non-transfected cells showed impaired aggregation, demonstrating that this variant disrupts the cell-adhesion function of N-cadherin.\",\n      \"method\": \"Stable transfection of L1 fibroblasts, quantitative cell aggregation assay\",\n      \"journal\": \"Endocrine connections\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with variant vs. wild-type comparison, single lab, single method\",\n      \"pmids\": [\"37166408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Endothelin-1 (EDN1) increases CDH2 expression in human mesenchymal stem cells through endothelin receptor A (EDNRA); promoter activity assays identified GATA2 and MZF1 as transcription factors that bind the CDH2 promoter and are required for EDN1-induced CDH2 upregulation; deletion or point mutation of GATA2 or MZF1 binding sequences abolished this promoter activity.\",\n      \"method\": \"CDH2 promoter activity assay, EDNRA blocker (BQ123), site-directed mutagenesis of promoter binding sites, western blot\",\n      \"journal\": \"Molecular therapy. Methods & clinical development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assay with mutagenesis identifies specific TF binding sites, pharmacological receptor blockade, single lab\",\n      \"pmids\": [\"31194009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nuclear translocation of the cleaved intracellular domain of PCDH9 interacts with DNMT1 and increases its activity, leading to increased DNA methylation at the CDH2 promoter and consequent downregulation of CDH2 expression, thereby reducing gastric cancer cell migration and in vivo metastasis.\",\n      \"method\": \"Co-immunoprecipitation (PCDH9 ICD–DNMT1), DNMT1 activity assay, bisulfite sequencing of CDH2 promoter, CDH2 expression rescue, in vivo metastasis model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus DNMT1 activity assay plus bisulfite sequencing plus functional rescue, single lab\",\n      \"pmids\": [\"38357662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In TM4 Sertoli cells, the AP-1 transcription factor Junb directly binds to AP-1 regulatory elements in the proximal Cdh2 promoter region; ChIP-qPCR and luciferase reporter assays with site-directed mutagenesis confirmed that Junb recruits to several AP-1 sites and that knockdown of Junb decreases Cdh2 expression.\",\n      \"method\": \"siRNA knockdown, ChIP-qPCR, luciferase reporter assay with site-directed mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP-qPCR plus luciferase with mutagenesis confirms direct TF–promoter interaction, single lab\",\n      \"pmids\": [\"37119763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"lncRNA SNHG15 preferentially localizes at cellular protrusions directed by IMP1; SNHG15 forms a complex with nucleolin and co-transports it to cell protrusions, where nucleolin binds CDH2 mRNA, stabilizes it locally, and enhances its translation, thereby promoting breast cancer cell invasion.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, proximity ligation, localization imaging, CDH2 mRNA stability and translation assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and Co-IP demonstrating complex, localization imaging, mRNA stability assay, single lab\",\n      \"pmids\": [\"37958584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARTEMIN promotes CDH2 expression via p44/42 MAP kinase signalling; siRNA depletion of CDH2 reduced ARTN-enhanced oncogenicity and chemoresistance to 5-FU, and forced CDH2 expression rescued the reduced mesenchymal properties after ARTN depletion, placing CDH2 downstream of ARTN/p44/42 MAPK in colorectal carcinoma.\",\n      \"method\": \"siRNA knockdown, forced expression, MAP kinase inhibition, cell invasion/migration assays, xenograft model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via rescue experiment plus pharmacological inhibition, single lab, multiple functional readouts\",\n      \"pmids\": [\"34422665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR/Cas9-mediated knockout of Cdh2 in 4T1 breast cancer cells confirmed absence of N-cadherin protein and significantly reduced tumor cell migration, establishing a direct role for CDH2 in cancer cell motility.\",\n      \"method\": \"CRISPR/Cas9 gene knockout, western blot confirmation, transwell migration assay\",\n      \"journal\": \"Pharmaceutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with protein confirmation and defined functional readout, single lab\",\n      \"pmids\": [\"35890278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In osteoblast-like MC3T3 cells, N-cadherin (CDH2) binds to PI3K components p85α and p110, restraining PI3K-Akt-β-catenin signalling; Cdh2 ablation enhances Tgf-β1-activated PI3K signalling, increases Tgf-β1 production via enhanced Sp1/Lef-1 binding to the Tgfb1 promoter, upregulates miR-21, and decreases PTEN, creating a pro-tumorigenic feed-forward loop that promotes breast cancer cell growth.\",\n      \"method\": \"Cdh2 ablation, Co-immunoprecipitation (CDH2–p85α/p110), PI3K activity assay, Tgfb1 promoter assay with ChIP (Sp1/Lef-1), miR-21 measurement, PTEN western blot, co-culture and co-injection tumor models, Tgfbr1 genetic ablation epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP identifies CDH2–PI3K binding, multiple orthogonal methods, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.22.683948\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ndrg1b promotes recycling of N-cadherin (cdh2) to the plasma membrane in zebrafish muscle cells; loss of Ndrg1b disrupts N-cadherin subcellular localization, impairs cell adhesion in vitro, and causes defective skeletal muscle morphogenesis phenotypically similar to cdh2 loss, identifying Ndrg1b as a component of the endocytic trafficking machinery for CDH2.\",\n      \"method\": \"Zebrafish morpholino/genetic knockdown of ndrg1b, N-cadherin localization imaging, cell aggregation assay, rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization imaging and aggregation assay in model organism, preprint only, no direct biochemical reconstitution of trafficking\",\n      \"pmids\": [\"bio_10.1101_2025.05.08.652902\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the DSG2 interactome of primary neonatal cardiomyocytes, over half of DSG2-associated proteins are shared with the N-cadherin (CDH2) interactome; plakoglobin (JUP) and plakophilin 2 (PKP2) were the most abundant proteins shared between DSG2 and CDH2 interactomes, suggesting CDH2 and DSG2 participate in overlapping adhesion complexes at the intercalated disc.\",\n      \"method\": \"Proximity labeling (BioID), quantitative mass spectrometry, interactome comparison\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling MS identifies interaction network but no direct binding validation for CDH2-specific partners; preprint\",\n      \"pmids\": [\"bio_10.1101_2025.06.09.658637\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In chick embryo dorsal forebrain neuroepithelium, Cdh2 spatiotemporal expression mirrors a tissue stiffness gradient during roof plate invagination; the interplay between Cdh2 and F-actin modulates tissue stiffness by regulating apical adherens junction stability and cortical F-actin distribution along the apico-basal axis, contributing to roof plate morphogenesis.\",\n      \"method\": \"Atomic force microscopy (tissue stiffness mapping), Cdh2 expression analysis, F-actin perturbation, adherens junction immunostaining in chick embryo\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — AFM stiffness mapping correlated with Cdh2 expression plus F-actin perturbation; preprint, no direct genetic ablation of Cdh2 reported in this study\",\n      \"pmids\": [\"bio_10.1101_2025.11.03.686203\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lncRNA MEG3 recruits the histone acetyltransferase EP300 to the CDH2 locus in hippocampal neurons of ASD rats, activating CDH2 transcription; CDH2 upregulation represses neuronal viability and promotes apoptosis in this model, and MEG3 knockdown ameliorated ASD-like learning/memory impairments through reduced CDH2.\",\n      \"method\": \"Microarray, ChIP (MEG3–EP300 recruitment to CDH2 promoter), CDH2 depletion, MEG3 knockdown in rat ASD model\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates EP300 recruitment to CDH2 promoter plus in vivo rescue experiments, single lab\",\n      \"pmids\": [\"35697159\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH2 (N-cadherin) is a transmembrane Ca2+-dependent cell adhesion molecule that mediates homophilic cell-cell adhesion via its extracellular HAV domain, anchors cortical F-actin through adherens junction complexes containing plakoglobin and plakophilin-2, and transduces intracellular signals by binding to and restraining PI3K components (p85α/p110) to suppress Akt-β-catenin signalling; its transcription is regulated by Hes7 (segmentation clock), FOXF1, AP-1/Junb, MEG3/EP300, and DNMT1-mediated promoter methylation, while its mRNA translation is controlled by ALKBH5-dependent m6A modification read by IGF2BP1/2/3 and YTHDF1; functionally, CDH2 is required for blood-testis barrier integrity, cortical progenitor proliferation control, interneuron migration and survival, presynaptic vesicle clustering and dopaminergic neurotransmission, FGF-dependent segmentation clock oscillations, and myosin-II-mediated tissue internalisation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDH2 (N-cadherin) is a Ca2+-dependent homophilic cell-cell adhesion molecule whose extracellular HAV-domain-mediated interactions assemble adherens junctions required for tissue integrity and morphogenesis across multiple developmental contexts [#2, #11]. Its adhesive function underpins the blood-testis barrier, where Sertoli-cell-specific loss disrupts basal ectoplasmic specializations, delays meiosis, and reduces sperm output [#1], and it controls cortical development by maintaining radial-glia adherens junctions that restrain progenitor proliferation and ensure proper lamination [#4]. Beyond static adhesion, CDH2 couples to actomyosin contractility to drive tissue shape change, acting upstream of Myosin-II during neural plate internalisation [#6]. In the segmentation clock, CDH2 is a direct transcriptional target of Hes7 and operates upstream of FGF signalling to sustain oscillations [#10], and in stem cells it stabilizes FGFR1 to support FGF-dependent self-renewal [#0] while promoting neural differentiation [#3]. In neurons CDH2 organizes presynaptic vesicle clustering and dopaminergic neurotransmission, and a maturation-impairing missense mutation causes familial ADHD [#9]. CDH2 also transduces intracellular signals by binding the PI3K subunits p85\\u03b1 and p110 to restrain Akt\\u2013\\u03b2-catenin signalling [#18]. Its expression is regulated transcriptionally by FOXF1 [#5], AP-1/Junb [#14], GATA2/MZF1 downstream of endothelin-1 [#12], and MEG3/EP300 [#22], and is silenced by DNMT1-mediated promoter methylation [#13], while its mRNA translation is controlled by ALKBH5-dependent m6A modification read by IGF2BP1/2/3 and YTHDF1 [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that CDH2-based adherens junctions, acting through the HAV homophilic interface, are required for epithelial cell survival rather than adhesion alone, and that CDH2 levels gate neural differentiation.\",\n      \"evidence\": \"HAV-domain blocking peptides in vivo with TUNEL readout; gain- and loss-of-function in mouse iPSCs with differentiation assays\",\n      \"pmids\": [\"23965744\", \"23416351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking junction disruption to apoptosis not defined\", \"Downstream effectors of CDH2 in differentiation not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed CDH2 restrains progenitor proliferation and enforces cortical lamination by maintaining radial-glia adherens junctions, linking adhesion to proliferation control.\",\n      \"evidence\": \"Conditional knockout in dorsal telencephalon with BrdU proliferation and histology, plus afadin co-inactivation\",\n      \"pmids\": [\"25100583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signalling pathway coupling junction loss to hyperproliferation not resolved\", \"How dispersed progenitors generate band heterotopia unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined CDH2 as a required structural component of the blood-testis barrier and as a stabilizer of FGFR1 supporting FGF-dependent stem-cell self-renewal, extending its role from adhesion to receptor regulation.\",\n      \"evidence\": \"Sertoli-cell conditional KO with BTB and meiosis readouts; reciprocal Co-IP and knockdown in mEpiSCs\",\n      \"pmids\": [\"25631347\", \"26420260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CDH2\\u2013FGFR1 interaction unknown\", \"Whether FGFR1 stabilization underlies BTB or differentiation roles untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FOXF1 as a direct transcriptional regulator that controls a CDH2-to-CDH11 cadherin switch governing myofibroblast invasion, establishing transcriptional control of CDH2 with functional consequences.\",\n      \"evidence\": \"Promoter ChIP, FOXF1 conditional KO mouse, CDH2 re-expression rescue, invasion assay\",\n      \"pmids\": [\"29642003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cadherin identity dictates invasive phenotype mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the regulatory landscape of CDH2 transcription and showed that point variants disrupt adhesion function, linking CDH2 to morphogenesis and disease.\",\n      \"evidence\": \"Promoter assays with mutagenesis identifying GATA2/MZF1 downstream of EDN1/EDNRA; L1 fibroblast aggregation assay of the p.Val289Ile hypopituitarism variant; zebrafish Myosin-II internalisation analysis\",\n      \"pmids\": [\"31194009\", \"37166408\", \"30755665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether adhesion defect alone explains hypopituitarism not established\", \"Molecular link between CDH2 and Myosin-II distribution undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided causal genetic evidence that a CDH2 maturation-impairing mutation causes ADHD via defective presynaptic vesicle clustering and dopaminergic deficits, defining a synaptic function for CDH2.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in mouse with behavior, electrophysiology, dopamine quantification and methylphenidate rescue; ARTN/p44-42 MAPK epistasis in colorectal cancer\",\n      \"pmids\": [\"34702855\", \"34422665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How impaired maturation produces vesicle-clustering defect not resolved\", \"Connection between adhesion and dopaminergic signalling unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established post-transcriptional control of CDH2 through m6A modification and demonstrated a direct requirement for CDH2 in cancer cell motility.\",\n      \"evidence\": \"m6A-seq, RIP-qPCR, polysome fractionation and Alkbh5-KO mouse with ultrastructure; CRISPR KO in 4T1 cells with migration assay\",\n      \"pmids\": [\"36418936\", \"35890278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether translational and adhesive roles of CDH2 are separable in cancer untested\", \"Site-specific m6A residues on Cdh2 mRNA not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned CDH2 within the segmentation clock as a direct Hes7 target acting upstream of FGF signalling, and identified AP-1/Junb as a direct promoter activator.\",\n      \"evidence\": \"Hes7 ChIP-seq, Cdh2 KO/overexpression in ESC-derived PSM with live Hes7 oscillation imaging; ChIP-qPCR and luciferase mutagenesis for Junb\",\n      \"pmids\": [\"40951951\", \"37119763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDH2 feeds back to modulate FGF signalling mechanistically unknown\", \"Relationship between CDH2 protein gradient and oscillatory output unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed epigenetic silencing of CDH2 via PCDH9-ICD-stimulated DNMT1 promoter methylation suppresses gastric cancer metastasis, adding a methylation-based regulatory layer.\",\n      \"evidence\": \"Co-IP, DNMT1 activity assay, bisulfite sequencing of CDH2 promoter, rescue and in vivo metastasis model\",\n      \"pmids\": [\"38357662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDH2 loss is necessary versus correlative for metastasis suppression unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a signalling output for CDH2 in which it binds PI3K subunits to restrain Akt-\\u03b2-catenin signalling, and implicated trafficking and adhesion-complex partners, extending CDH2 beyond junctional adhesion.\",\n      \"evidence\": \"Co-IP of CDH2 with p85\\u03b1/p110, PI3K and promoter assays in osteoblast-like cells (preprint); zebrafish Ndrg1b recycling study (preprint); DSG2/CDH2 interactome by BioID-MS identifying JUP and PKP2 (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.22.683948\", \"bio_10.1101_2025.05.08.652902\", \"bio_10.1101_2025.06.09.658637\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PI3K-restraint model from a single preprint without independent confirmation\", \"Trafficking and intercalated-disc partner claims lack direct CDH2 binding validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDH2's adhesive, mechanotransductive, receptor-stabilizing, and signalling functions are integrated within a single tissue context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model unifying CDH2 binding to FGFR1, PI3K, and junctional partners\", \"Whether intracellular signalling roles are conserved beyond bone/cancer cells untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 19]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [\"adherens junction\"],\n    \"partners\": [\"FGFR1\", \"PIK3R1\", \"PIK3CA\", \"JUP\", \"PKP2\", \"DSG2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}