{"gene":"VGF","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":1991,"finding":"VGF gene transcription is rapidly and selectively induced by NGF (and basic FGF) in PC12 cells via a cAMP response element (CRE) in the promoter; induction also occurs with depolarization and PMA. The promoter contains TATAA, CCAAT elements, GC boxes, and a consensus CRE-binding protein site.","method":"Northern/RNase protection analysis, promoter cloning and sequencing, transcription reporter assays in PC12 cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — promoter characterization with multiple methods, replicated across labs","pmids":["2017159"],"is_preprint":false},{"year":1992,"finding":"NGF induces VGF gene expression at the transcriptional level through a consensus CRE embedded in a 14-bp palindrome immediately upstream of the transcription start site; mutation of this CRE eliminates induction by both NGF and cAMP. This element selectively responds to NGF/cAMP but not EGF, FGF, or PMA. The inducible transcription factor CREB binds this CRE.","method":"Promoter mutagenesis, transient transfection reporter assays, EMSA (CREB binding), pharmacological treatments in PC12 cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis plus EMSA plus functional transcription assay in same study","pmids":["1377233"],"is_preprint":false},{"year":1992,"finding":"VGF gene induction by NGF requires ongoing protein synthesis (transcription-dependent), is partly repressed in non-neuronal cells by a nuclear repressor, and a 110-bp promoter region contains both positive and negative regulatory elements. A 47-bp oligonucleotide within this region specifically binds nuclear proteins that differ between VGF-expressing and non-expressing cells.","method":"Transcriptional run-on, promoter-reporter transfection, EMSA with cell-type-specific nuclear extracts, protein synthesis inhibition","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods establishing transcriptional mechanism","pmids":["1570299"],"is_preprint":false},{"year":1995,"finding":"VGF precursor undergoes tissue-specific proteolytic processing in a post-ER compartment to produce low-molecular-weight species (~20, 18, 10 kDa). These processed forms are enriched in secretory vesicles and preferentially secreted upon membrane depolarization, indicating regulated release from dense core vesicles.","method":"Immunoblotting with N- and C-terminal antisera, subcellular fractionation, depolarization-induced secretion assays in cerebellar granule cells and PC12 cells","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1/2 — fractionation plus functional secretion assay, multiple cell types","pmids":["7595538"],"is_preprint":false},{"year":1996,"finding":"VGF transcriptional induction by NGF is mediated through a Ras-dependent signaling pathway. Three promoter elements are required: a CRE (binding ATF-1, ATF-2, CREB), a novel CCAAT element, and a G(S)G element between the TATA box and transcription start site that binds the NGF/Ras-induced transcription factor NGFI-A. All three are necessary but no single element is sufficient.","method":"Chimeric vgf/beta-globin reporter gene transfection, dominant-interfering and activated Ras mutants, TrkA mutants, promoter deletional/mutational analysis, EMSA","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis plus genetic (Ras pathway) epistasis in same study","pmids":["8756618"],"is_preprint":false},{"year":1997,"finding":"VGF promoter regulation involves cooperative binding of an E-box (binding HTF4/HEB E-protein as part of a multiprotein complex) and a CRE; the E-box acts as a repressor in non-neuronal (NIH 3T3) cells but as a stimulator in NGF-responsive PC12 cells. A neuro-specific bHLH transcription factor (MASH1) participates in neurotrophin-dependent transcription via the CCAAT motif.","method":"EMSA, expression cDNA cloning, reporter gene transfection, mutational analysis of E-box and CRE","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — biochemical isolation of binding factors plus mutagenesis in same study","pmids":["9032251"],"is_preprint":false},{"year":1999,"finding":"VGF knockout mice are lean, hypermetabolic, hyperactive, and infertile with markedly reduced leptin levels, fat stores, and altered hypothalamic POMC, NPY, and AGRP expression, establishing a non-redundant role for VGF in energy homeostasis. VGF mRNA is induced in hypothalamic arcuate nuclei upon fasting.","method":"Targeted gene deletion (knockout mice), metabolic phenotyping, in situ hybridization","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — clean germline KO with defined multi-system metabolic phenotype, highly cited foundational paper","pmids":["10433265"],"is_preprint":false},{"year":1999,"finding":"VGF is expressed in insulin-secreting INS-1 beta cells, where it is processed in a post-ER compartment and its peptides are released via a regulated secretory pathway upon stimulation with glucose, cAMP, or PMA. VGF mRNA in INS-1 cells is transcriptionally upregulated by increased intracellular cAMP but not by glucose or NGF.","method":"RT-PCR, metabolic labeling, immunoprecipitation, secretion assays in INS-1 cells","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (transcription + secretion) in same study","pmids":["10433233"],"is_preprint":false},{"year":2002,"finding":"PC1/3 and PC2 prohormone convertases process the VGF precursor: both generate VGF20 (a ~20 kDa C-terminal fragment), while VGF10 is preferentially produced by PC1/3. The KRKRKK(488) motif is the target cleavage site generating VGF20 (identified by site-directed mutagenesis); VGF10 results from cleavage at RPR(555). Two additional novel VGF peptides were identified in rat brain by MALDI-ToF MS and Edman degradation.","method":"Ectopic expression of PC1/3 or PC2 in GH3 cells, site-directed mutagenesis of VGF cleavage sites, MALDI-ToF MS, Edman degradation","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution (ectopic PC expression) plus mutagenesis plus MS structural identification","pmids":["12065665"],"is_preprint":false},{"year":2002,"finding":"VGF and POMC are co-expressed in lateral arcuate neurons in fed state; VGF expression is induced in medial arcuate NPY neurons after fasting. VGF mRNA induction in fasted mice is inhibited by exogenous leptin, and is elevated in leptin-deficient ob/ob and db/db mice. VGF deficiency completely blocks obesity in agouti (Ay/a) mice but only attenuates weight gain in ob/ob mice, placing VGF downstream of melanocortin 4 receptors in autonomic outflow pathways.","method":"Double-label in situ hybridization, genetic epistasis (VGF KO × Ay/a, ob/ob, db/db crosses), leptin injection, gold thioglucose and diet-induced obesity models","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — epistasis in multiple genetic models with pathway placement","pmids":["12177191"],"is_preprint":false},{"year":2002,"finding":"NGF-dependent and tissue-specific transcription of vgf is regulated by a CREB-p300 complex and a bHLH factor interaction. In non-neuronal cells, HEB (ubiquitous bHLH) and p300 form a repressor complex at the promoter. In neuronal cells, neurotrophin-dependent transcription is mediated by a distinct complex containing CREB, MASH1 (neuro-specific bHLH), and p300 bound to the CCAAT motif.","method":"Co-immunoprecipitation, EMSA, chromatin immunoprecipitation, reporter gene transfection, dominant-negative approaches","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1/2 — protein complex identification plus functional reporter assays","pmids":["11755530"],"is_preprint":false},{"year":2005,"finding":"VGF sorting into the regulated secretory pathway (large dense core vesicles, LDCVs) requires a compact C-terminal alpha-helix and an embedded 564RRR566 prohormone convertase cleavage site. Mutation of 564RRR566 blocks regulated secretion; mutation of adjacent 567HFHH570 also blocks regulated release. Inhibition of PC cleavage by membrane-permeable chloromethyl ketone (decanoyl-RVKR-CMK) blocks regulated VGF secretion.","method":"Deletional and site-directed mutagenesis of VGF, confocal microscopy, subcellular fractionation, pharmacological PC inhibition in PC12 and INS-1 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis plus cell biology of trafficking with multiple cell types","pmids":["16221685"],"is_preprint":false},{"year":2006,"finding":"The VGF-derived peptide TLQP-21 (identified in rat brain by immunoprecipitation/LC-MS/MS) increases resting energy expenditure and rectal temperature upon chronic ICV injection in mice, preventing diet-induced obesity. TLQP-21 acts by stimulating autonomic activation of the adrenal medulla, upregulating brown adipose tissue beta2-AR and white adipose tissue PPAR-delta, beta3-AR, and UCP1 mRNAs, independently of thyroid hormones or locomotor activity.","method":"LC-MS/MS peptide identification, chronic ICV injection, indirect calorimetry, gene expression (RT-PCR), hormonal measurements","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — endogenous peptide identified by MS, functional mechanism characterized by multiple molecular readouts","pmids":["16983076"],"is_preprint":false},{"year":2008,"finding":"The VGF C-terminal peptide TLQP-62 induces transient potentiation in rat hippocampal slices through a mechanism blocked by the BDNF scavenger TrkB-Fc, Trk kinase inhibitor K252a, and tPA inhibitor tPASTOP, but not by NMDA receptor antagonist APV or anti-p75NTR. VGF knockout mice cannot undergo hippocampal LTD and show impaired spatial learning and contextual fear conditioning.","method":"Electrophysiology in hippocampal slices (LTP/LTD), pharmacological blockade with specific inhibitors, VGF KO behavioral testing (Morris water maze, fear conditioning)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — pharmacological dissection of signaling pathway plus KO phenotype in same study","pmids":["18815270"],"is_preprint":false},{"year":2009,"finding":"VGF-derived peptides AQEE-30 and LQEQ-19 evoke dose-dependent thermal hyperalgesia upon intrathecal injection via activation of p38 MAP kinase. LQEQ-19 induces p38 phosphorylation in spinal microglia in vivo and in BV-2 microglial cells in vitro. VGF protein levels are rapidly upregulated in dorsal root ganglion neurons after nerve injury and hindpaw inflammation.","method":"Intrathecal peptide injection, thermal hyperalgesia assays, p38 immunostaining/phospho-western, proteomics of DRG neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo and in vitro assays linking VGF peptides to p38-dependent nociceptive signaling","pmids":["19846725"],"is_preprint":false},{"year":2009,"finding":"NERP-1 and NERP-2, novel bioactive peptides derived from VGF, co-localize with vasopressin in storage granules of paraventricular and supraoptic hypothalamic nuclei. Administration of NERPs suppresses vasopressin release from hypothalamus and pituitary induced by hypertonic saline or angiotensin II.","method":"Immunohistochemistry/co-localization, in vivo and ex vivo vasopressin secretion assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — co-localization plus in vivo functional secretion assay, single lab","pmids":["19194657"],"is_preprint":false},{"year":2012,"finding":"TLQP-21 promotes lipolysis in murine white adipose tissue (WAT) via a saturable receptor-binding mechanism that requires activation of noradrenaline/beta-adrenergic receptor pathways. VGF immunoreactivity is present in sympathetic nerve fibers innervating WAT but not in adipocytes. TLQP-21 binding capacity is higher in WAT than other tissues and is upregulated in obese mice.","method":"Receptor binding assays (saturation binding), lipolysis assays in primary adipocytes, immunohistochemistry, in vivo injection in obesity models","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 — receptor binding plus mechanistic pharmacology plus in vivo, multiple orthogonal methods","pmids":["21880012"],"is_preprint":false},{"year":2012,"finding":"Nkx6.1 strongly upregulates VGF in rat islets, and VGF is necessary and sufficient for Nkx6.1-mediated enhancement of glucose-stimulated insulin secretion (GSIS). The VGF-derived peptide TLQP-21 potentiates GSIS in rat and human islets and improves glucose tolerance in vivo. Chronic TLQP-21 injection in prediabetic ZDF rats preserves islet mass. TLQP-21 prevents islet apoptosis by a GLP-1/GIP/VIP receptor-independent pathway similar to that of GLP-1.","method":"Overexpression/knockdown of VGF in rat islets, GSIS assays, receptor antagonist studies, in vivo ZDF rat treatment, apoptosis assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function plus mechanistic pharmacology in islets and in vivo","pmids":["22768837"],"is_preprint":false},{"year":2013,"finding":"C3a receptor-1 (C3AR1) is a G protein-coupled receptor target for the VGF-derived peptide TLQP-21 in rodent cells. Identified by unbiased genome-wide transcriptome sequencing of responsive CHO-K1 cells, confirmed by siRNA knockdown and receptor antagonists. TLQP-21 signaling through C3AR1 is pertussis toxin-sensitive (consistent with Gi/o coupling) and directs migration of mouse RAW264.7 macrophages.","method":"Unbiased RNA-seq-based receptor deorphanization, siRNA knockdown, receptor antagonists, pertussis toxin, cell migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — unbiased screen plus genetic (siRNA) and pharmacological validation, multiple functional readouts","pmids":["23940034"],"is_preprint":false},{"year":2013,"finding":"gC1qR (globular heads of the C1q receptor) is a receptor for the VGF-derived peptide TLQP-21, identified by chemical cross-linking combined with mass spectrometry. TLQP-21 causes increased intracellular Ca2+ in rat macrophages and microglia via gC1qR. TLQP-21-stimulated macrophages cause mechanical hypersensitivity when inoculated into rat hind paw; gC1qR-neutralizing antibody attenuates neuropathic pain in partial sciatic nerve ligation.","method":"Chemical cross-linking/mass spectrometry, siRNA knockdown, neutralizing antibodies, intracellular Ca2+ imaging, in vivo pain model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — chemical cross-linking/MS receptor identification plus genetic and pharmacological validation plus in vivo pain model","pmids":["24106277"],"is_preprint":false},{"year":2014,"finding":"TLQP-21 induces thermal hyperalgesia via p38 MAP kinase and is inhibited by cyclooxygenase and lipoxygenase inhibitors. Immunoneutralization of endogenous TLQP-21 by intrathecal anti-TLQP-21 antibody inhibits tactile hypersensitivity and thermal hyperalgesia in CFA-induced inflammation and spared nerve injury neuropathic pain models, demonstrating that endogenous TLQP-21 contributes to spinal pain sensitization.","method":"Intrathecal peptide/antibody administration, von Frey and thermal withdrawal assays, pharmacological inhibitors (p38, COX, LOX) in CFA and SNI mouse models","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 — immunoneutralization of endogenous peptide plus pharmacological pathway dissection in two in vivo models","pmids":["24657450"],"is_preprint":false},{"year":2014,"finding":"The granin VGF promotes biogenesis of large dense core vesicles (LDCVs) in the adrenal medulla. VGF knockout mice have decreased LDCV size in noradrenergic chromaffin cells, increased adrenal norepinephrine and epinephrine content, elevated plasma epinephrine, decreased adrenal chromogranin B, and hypertension. Expression of exogenous VGF in NIH 3T3 fibroblasts generates LDCV-like structures with depolarization-induced secretion. Knock-in of human VGF1-615 rescues the hypertensive phenotype; knock-in of truncated VGF1-524 (lacking TLQP-21) only partially rescues it. Acute and chronic TLQP-21 administration decreases blood pressure.","method":"Germline VGF KO and humanized knock-in mice, electron microscopy of adrenal chromaffin cells, catecholamine measurements, blood pressure telemetry, VGF overexpression in NIH 3T3 fibroblasts, peptide administration","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1/2 — reconstitution in fibroblasts + genetic rescue with knock-in alleles + ultrastructural analysis","pmids":["24497580"],"is_preprint":false},{"year":2015,"finding":"VGF expression and secretion of C-terminal peptide TLQP-62 in hippocampus are transiently induced after fear memory training. Sequestering TLQP-62 after training impairs memory formation. TLQP-62 induces acute TrkB receptor phosphorylation and subsequent CREB phosphorylation in hippocampal slices. TLQP-62's memory-enhancing effect is rescued by BDNF-TrkB signaling activation and is VGF-dependent (germline or antibody-sequestration experiments). VGF-deficient mice show impaired Rac1 induction and reduced cofilin/synapsin phosphorylation after learning.","method":"In vivo fear conditioning, intra-hippocampal antibody infusion, hippocampal slice TrkB phosphorylation assays, VGF KO mice, BDNF rescue experiments, signaling pathway analysis (Rac1, cofilin, synapsin)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (KO, antibody sequestration, pathway rescue, electrophysiology) in same study","pmids":["26180209"],"is_preprint":false},{"year":2017,"finding":"VGF regulates insulin secretory granule biogenesis in pancreatic beta cells. Conditional VGF knockout in islets and beta-cell-specific knockout mice show profound decreases in stimulus-coupled insulin secretion. VGF is required for efficient exit of granule cargo from the trans-Golgi network, for proinsulin processing, and for replenishment of insulin granule stores after nutrient stimulation.","method":"Conditional KO (floxed VGF mice + Cre), islet secretion assays, electron microscopy of secretory granules, proinsulin processing analysis, trans-Golgi network trafficking assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1/2 — conditional KO with defined cellular granule biogenesis phenotype plus trafficking assays","pmids":["28877479"],"is_preprint":false},{"year":2017,"finding":"VGF regulates depression-like behavior in dorsal hippocampus (dHc) and nucleus accumbens (NAc) in opposite directions: dHc VGF ablation produces pro-depressant behavior and dHc VGF overexpression produces antidepressant behavior; NAc VGF ablation is antidepressant and overexpression is pro-depressant. The antidepressant efficacy of ketamine requires VGF expression and is associated with rapid VGF translation. TLQP-62 antidepressant effects in dHc require AMPA receptor and mTOR signaling (blocked by NBQX and rapamycin). Conditional pan-neuronal (but not forebrain) VGF ablation increases stress susceptibility, indicating neuronal (partially inhibitory interneuron) VGF regulates depression.","method":"AAV-Cre conditional KO and overexpression in floxed VGF mice (region-specific), germline VGF heterozygous mice, social defeat stress, forced swim test, AMPA/mTOR pharmacological inhibitors, Synapsin-Cre and αCaMKII-Cre crosses","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — conditional region-specific KO/OE with multiple genetic and pharmacological controls establishing pathway placement","pmids":["29158577"],"is_preprint":false},{"year":2020,"finding":"TLQP-21 increases motility and phagocytic capacity in murine microglia via C3aR1 signaling. C3aR1-null primary microglia have impaired basal phagocytic function; TLQP-21 and C3a super agonist induce overlapping transcriptomic changes (migration/proliferation genes) in wild-type but not C3aR1-null microglia. ICV TLQP-21 in 5xFAD mice reduces amyloid plaques, associated dystrophic neurites, and restores Alzheimer-associated microglial gene expression. Human TLQP-21 activates human microglia similarly to mouse TLQP-21.","method":"Phagocytosis/migration assays, RNA-seq of primary microglia (WT vs. C3aR1-null), osmotic pump ICV delivery in 5xFAD mice, immunohistochemistry for amyloid plaques, human HMC3 microglial cell line assays","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 2 — genetic (C3aR1 KO) and pharmacological validation, transcriptomics, and in vivo rescue in AD model","pmids":["31924226"],"is_preprint":false},{"year":2020,"finding":"TLQP-21 impairs metabotropic purinergic (P2Y) signaling in microglia in acute brain slices, attenuating ATP-induced K+ conductance, UDP-stimulated phagocytosis, and ATP-dependent process outgrowth toward injury. These impairments are reversed by blocking C1qBP but not C3aR1. In cultured microglia (which express both receptors), TLQP-21 additionally evokes Ca2+ transients, membrane currents, and chemotaxis via C3aR1, demonstrating dual receptor-dependent effects.","method":"Whole-cell patch clamp in brain slices, phagocytosis assays, laser lesion-induced process outgrowth imaging, Ca2+ imaging, C1qBP and C3aR1 antagonists, primary microglia from C3aR1-null mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — electrophysiology plus Ca2+ imaging plus genetic (C3aR1-null) and pharmacological (C1qBP antagonist) dissection in same study","pmids":["32060170"],"is_preprint":false},{"year":2020,"finding":"SOX9 drives injury-induced transcriptional upregulation of VGF in renal tubular epithelial cells (RTECs). RTEC-specific Vgf gene ablation exacerbates ischemia-, cisplatin-, and rhabdomyolysis-induced acute kidney injury in vivo and cisplatin-induced RTEC death in vitro. Aggravation of cisplatin injury by Vgf ablation is partly reversed by exogenous TLQP-21 peptide.","method":"Renal transcriptome profiling in three AKI mouse models, RTEC-specific conditional KO, in vitro cell death assays, SOX9 ChIP/reporter assays, TLQP-21 rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — conditional KO in three AKI models plus upstream transcription factor identification and peptide rescue","pmids":["32887795"],"is_preprint":false},{"year":2021,"finding":"TLQP-62 or contextual fear memory training acutely increases translation of VGF and other granin proteins (CgB, Scg2) via mTOR-dependent signaling without measurable increases in mRNA, constituting a transcription-independent autofeedback mechanism. The 3'UTR of Vgf mRNA represses VGF translation (validated by luciferase reporter). Mice with truncated endogenous Vgf 3'UTR show substantially increased VGF protein, enhanced memory performance, and reduced anxiety/depression-like behaviors.","method":"Polysome/translation assays, luciferase 3'UTR reporter assays, Vgf 3'UTR-truncation knock-in mice, mTOR inhibition (rapamycin), fear conditioning behavioral assays","journal":"Translational psychiatry","confidence":"High","confidence_rationale":"Tier 1 — reporter mutagenesis plus knock-in genetic model plus pharmacological inhibition establishing translational mechanism","pmids":["34238925"],"is_preprint":false},{"year":2008,"finding":"The VGF-derived peptide TLQP-21 promotes survival of rat cerebellar granule cells (CGCs) against serum/potassium deprivation-induced apoptosis in a dose- and time-dependent manner. Neuroprotection is associated with activation of ERK1/2, Akt (serine/threonine kinase), and JNK phosphorylation, decreased PKC phosphorylation, and increased intracellular Ca2+ in ~60% of neurons.","method":"Cell viability assays, DNA fragmentation (apoptosis), western blot for kinase phosphorylation, fura-2AM Ca2+ imaging in primary CGC cultures","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, pharmacological and biochemical readouts but no receptor identification or genetic validation","pmids":["18173805"],"is_preprint":false},{"year":2014,"finding":"TLQP-62 induces proliferation of early-phase (Type 2a nestin+) neural progenitor cells in the adult hippocampus via NMDA receptor- and mGluR5-dependent glutamate signaling, activating CaMKII and PKD, respectively. TLQP-62 also gradually activates TrkB (BDNF receptor), and TrkB signaling is required for TLQP-62-induced NPC proliferation.","method":"Nestin-GFP reporter mice, BrdU/thymidine incorporation, NPC proliferation assays in vitro (cell line and primary progenitors), pharmacological NMDA/mGluR5/CaMKII/PKD inhibitors, Cyclin D qPCR, TrkB inhibitors","journal":"Stem cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple pharmacological pathway dissections plus in vivo reporter mouse in same study","pmids":["24747217"],"is_preprint":false},{"year":2016,"finding":"Voluntary running induces VGF expression in the brain, which promotes oligodendrogenesis in the cerebellum of Snf2h conditional knockout ataxic mice, prolonging survival. VGF neuropeptides promote oligodendrogenesis in vitro, and adenoviral VGF overexpression in vivo rescues survival without requiring exercise.","method":"Conditional Snf2h KO mice, voluntary wheel running, VGF adenoviral overexpression, oligodendrocyte lineage cell counts, in vitro oligodendrogenesis assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic rescue (adenoviral VGF) phenocopies exercise effect plus in vitro mechanistic validation","pmids":["27732860"],"is_preprint":false},{"year":2009,"finding":"TLQP-21 induces contraction of rat forestomach smooth muscle by releasing prostaglandins PGE2 and PGF2a from the mucosal layer, blocked by indomethacin and selective COX-1/COX-2 inhibitors. ICV TLQP-21 decreases gastric emptying by ~40% via central PG release. VGF immunoreactivity is present in gastric neuronal cells.","method":"Isolated smooth muscle preparation, in vitro contraction assays, pharmacological inhibitors (indomethacin, COX-1/2), in vivo ICV injection, gastric emptying measurement, immunostaining","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro pharmacological mechanism plus in vivo, but single lab","pmids":["19466987"],"is_preprint":false},{"year":2018,"finding":"VGF and TLQP-62 in ventromedial prefrontal cortex (vmPFC) regulate stress susceptibility and antidepressant response to ketamine. TLQP-62 antidepressant-like effects in vmPFC require BDNF expression and calcium mobilization (blocked by xestospongin C, an IP3 receptor inhibitor, and SKF96365, a TRPC/store-operated channel inhibitor), revealing a calcium-dependent signaling mechanism downstream of TLQP-62/BDNF.","method":"AAV-Cre conditional VGF KO and overexpression in floxed VGF mice (vmPFC), intra-vmPFC TLQP-62 infusion, Bdnf conditional KO, pharmacological Ca2+ pathway inhibitors, chronic restraint stress, subchronic variable stress","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 — region-specific conditional genetics plus pharmacological dissection of Ca2+ mechanism in same study","pmids":["30504797"],"is_preprint":false},{"year":2019,"finding":"lncRNA H19 binds VGF protein (demonstrated by RNA pulldown and mass spectrometry) and promotes pancreatic neuroendocrine neoplasm (pNEN) cell proliferation, migration and invasion. VGF activated PI3K/AKT/CREB signaling; H19 activates this signaling pathway via VGF, and VGF knockdown reduces these oncogenic phenotypes.","method":"RNA pulldown/mass spectrometry, RIP, siRNA knockdown, in vitro proliferation/migration/invasion assays, RNA-seq, in vivo xenograft","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 3 — RNA pulldown/MS identifying lncRNA-VGF interaction plus functional knockdown, single lab","pmids":["31117050"],"is_preprint":false},{"year":1989,"finding":"VGF immunoreactivity in the hypothalamus co-localizes with vasopressin or vasoactive intestinal polypeptide in SCN neurons, and with oxytocin or vasopressin in paraventricular and supraoptic nuclei. Ultrastructural studies show VGF immunoreactivity in presynaptic boutons in SCN and in axons of the neurohypophysis, consistent with a secretory neuropeptide role.","method":"Immunocytochemistry with two non-overlapping antisera, colchicine axonal transport blockade, co-localization by immunofluorescence, electron microscopy","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple antisera, ultrastructural localization, co-localization in defined cell types, highly cited","pmids":["2556505"],"is_preprint":false},{"year":1996,"finding":"VGF is localized to a subpopulation of large dense core vesicles in PC12 cells (by electron microscopy). In developing hippocampal neurons, VGF-containing vesicles are present from earliest developmental stages and are particularly abundant in GABAergic neurons; VGF becomes restricted to axons after dendrites mature (associated with synaptogenesis, not axonal polarization). VGF-containing and synaptophysin-containing vesicles are distinct and differentially distributed.","method":"Electron microscopy immunolabeling in PC12 cells, immunofluorescence co-localization in hippocampal neurons, developmental staging","journal":"Brain research. Developmental brain research","confidence":"Medium","confidence_rationale":"Tier 2 — ultrastructural localization plus developmental co-localization, single lab","pmids":["8922684"],"is_preprint":false}],"current_model":"VGF is a neurotrophin (NGF/BDNF)-inducible, activity-regulated secreted neuropeptide precursor that is transcriptionally controlled via a CREB/CRE-dependent promoter (additionally regulated by Ras/NGFI-A, HEB/MASH1-p300 bHLH complexes), sorted into large dense core vesicles through a C-terminal RRR prohormone convertase site, proteolytically processed by PC1/3 and PC2, and secreted in a regulated manner; its bioactive C-terminal peptides (especially TLQP-21 and TLQP-62) act on G protein-coupled receptors (C3aR1, gC1qR/C1qBP) to modulate energy balance and lipid metabolism through sympathoadrenal pathways, promote hippocampal synaptic plasticity and memory consolidation via a BDNF-TrkB positive feedback loop requiring mTOR-dependent translation and AMPA receptor insertion, regulate microglial phagocytosis and motility through C3aR1/purinergic signaling, control insulin granule biogenesis and secretion in beta cells, and exert pro-nociceptive effects in the spinal cord through p38 MAP kinase activation in microglia."},"narrative":{"teleology":[{"year":1989,"claim":"Before VGF's molecular function was known, ultrastructural co-localization with vasopressin and oxytocin in hypothalamic neurosecretory terminals established it as a candidate secreted neuropeptide rather than an intracellular signaling protein.","evidence":"Immunocytochemistry with two antisera plus electron microscopy in rat hypothalamus","pmids":["2556505"],"confidence":"High","gaps":["No identification of processed peptides","Secretion stimulus not tested","Function of VGF in these neurons unknown"]},{"year":1992,"claim":"Defining how neurotrophin signals reach the VGF locus, studies showed that a CRE immediately upstream of the transcription start site is both necessary and sufficient for NGF/cAMP-mediated induction, with CREB binding this element—establishing VGF as a direct CREB target gene.","evidence":"Promoter mutagenesis, EMSA for CREB binding, and transcription reporter assays in PC12 cells","pmids":["2017159","1377233","1570299"],"confidence":"High","gaps":["Chromatin-level regulation not addressed","In vivo relevance of CRE not tested"]},{"year":1996,"claim":"The question of how multiple cis-elements cooperate was resolved by showing that NGF-induced VGF transcription requires three elements—CRE, CCAAT, and a G(S)G element binding the Ras-induced factor NGFI-A—none sufficient alone, placing VGF downstream of the Ras-MAPK cascade.","evidence":"Chimeric reporter mutagenesis, dominant-negative Ras, TrkA mutants, EMSA in PC12 cells","pmids":["8756618"],"confidence":"High","gaps":["Relative contribution of each element in vivo undetermined","Post-translational modifications of NGFI-A at VGF promoter not characterized"]},{"year":1997,"claim":"Cell-type restriction of VGF expression was explained by the finding that the E-box/CCAAT region recruits a repressive HEB complex in non-neuronal cells but a stimulatory MASH1-p300 complex in neuronal cells, later shown to involve CREB-p300 cooperation for neurotrophin-dependent activation.","evidence":"EMSA, expression cloning, reporter mutagenesis, co-immunoprecipitation, and ChIP","pmids":["9032251","11755530"],"confidence":"High","gaps":["Epigenetic marks distinguishing repressor vs. activator states not mapped","In vivo ChIP not performed"]},{"year":1995,"claim":"The question of whether VGF is a regulated secretory molecule was answered: VGF precursor undergoes tissue-specific post-ER cleavage into low-MW peptides enriched in secretory vesicles and preferentially released upon depolarization, confirming regulated dense-core vesicle secretion.","evidence":"Subcellular fractionation, immunoblotting with domain-specific antisera, depolarization-induced secretion in cerebellar granule and PC12 cells","pmids":["7595538"],"confidence":"High","gaps":["Convertases responsible not yet identified","Sorting signals not mapped"]},{"year":2002,"claim":"The identity of VGF-processing enzymes was established: PC1/3 and PC2 cleave VGF at KRKRKK(488) and RPR(555) to generate the major C-terminal fragments VGF20 and VGF10, and novel brain peptides were structurally identified by mass spectrometry.","evidence":"Ectopic PC1/3 and PC2 expression in GH3 cells, site-directed mutagenesis, MALDI-ToF MS and Edman degradation of rat brain extracts","pmids":["12065665"],"confidence":"High","gaps":["Full peptidomic catalogue of VGF-derived peptides incomplete","Tissue-specific differences in processing not fully mapped"]},{"year":2005,"claim":"The sorting mechanism was resolved: a C-terminal alpha-helix containing the 564RRR566 convertase site and adjacent 567HFHH570 residues are required for VGF entry into the regulated secretory pathway, linking prohormone processing to vesicular trafficking.","evidence":"Systematic mutagenesis, confocal imaging, subcellular fractionation, PC inhibitor in PC12 and INS-1 cells","pmids":["16221685"],"confidence":"High","gaps":["Chaperone or adaptor mediating recognition of this signal unknown","Whether this mechanism generalizes to all tissues not tested"]},{"year":1999,"claim":"The first physiological role was established: VGF knockout mice are lean, hypermetabolic, hyperactive, and infertile, demonstrating a non-redundant requirement for VGF in energy homeostasis and reproduction.","evidence":"Germline VGF KO mice, metabolic phenotyping, in situ hybridization for hypothalamic neuropeptides","pmids":["10433265"],"confidence":"High","gaps":["Which VGF-derived peptide(s) mediate the metabolic phenotype unknown","CNS vs. peripheral contributions not separated"]},{"year":2002,"claim":"VGF was placed in the melanocortin pathway: genetic epistasis showed VGF deficiency blocks obesity in agouti (Ay/a) mice but only attenuates it in ob/ob mice, positioning VGF downstream of MC4R signaling in autonomic outflow circuits.","evidence":"Double-mutant crosses (VGF KO × Ay/a, ob/ob, db/db), in situ hybridization, leptin injection","pmids":["12177191"],"confidence":"High","gaps":["Direct MC4R-to-VGF transcriptional mechanism not shown","Peripheral VGF contributions not excluded"]},{"year":2006,"claim":"The first bioactive VGF peptide was functionally characterized: ICV TLQP-21 increases energy expenditure and prevents diet-induced obesity by stimulating sympathoadrenal activation of brown and white adipose tissue, independent of thyroid hormones.","evidence":"LC-MS/MS peptide identification from brain, chronic ICV infusion, indirect calorimetry, adipose gene expression, hormonal measurements in mice","pmids":["16983076"],"confidence":"High","gaps":["Receptor for TLQP-21 not yet identified","Direct vs. indirect sympathetic activation not distinguished"]},{"year":2008,"claim":"TLQP-62 was shown to modulate hippocampal synaptic plasticity: it induces transient potentiation through a BDNF-TrkB-dependent mechanism (blocked by TrkB-Fc and tPA inhibition), and VGF KO mice lack hippocampal LTD and have impaired spatial learning and fear memory.","evidence":"Electrophysiology in hippocampal slices, pharmacological blockade, VGF KO behavioral testing","pmids":["18815270"],"confidence":"High","gaps":["Direct receptor for TLQP-62 not identified","Whether TLQP-62 acts pre- or post-synaptically unknown"]},{"year":2009,"claim":"VGF peptides were linked to pain signaling: AQEE-30 and LQEQ-19 evoke thermal hyperalgesia via p38 MAPK activation specifically in spinal microglia, and VGF is upregulated in DRG neurons after nerve injury, establishing VGF as a pro-nociceptive mediator.","evidence":"Intrathecal peptide injection, thermal assays, p38 immunostaining in spinal cord, DRG proteomics","pmids":["19846725"],"confidence":"High","gaps":["Receptor mediating spinal microglial activation not identified","Whether VGF peptides act as neuron-to-microglia signals in vivo not proven"]},{"year":2013,"claim":"Two receptors for TLQP-21 were identified: C3aR1 (a GPCR with Gi/o coupling) deorphanized by unbiased RNA-seq screening, and gC1qR/C1qBP identified by chemical cross-linking/MS, establishing the first direct receptor-ligand relationships for VGF-derived peptides.","evidence":"Genome-wide RNA-seq deorphanization, siRNA knockdown, chemical cross-linking/MS, receptor antagonists, Ca2+ imaging, macrophage migration, and in vivo pain models","pmids":["23940034","24106277"],"confidence":"High","gaps":["Relative contribution of C3aR1 vs. gC1qR in different tissues not systematically compared","Structural basis of TLQP-21 binding to either receptor unknown"]},{"year":2014,"claim":"VGF was shown to be a granin that drives dense-core vesicle biogenesis: VGF KO adrenal chromaffin cells have smaller LDCVs, while VGF expression in fibroblasts generates LDCV-like structures with regulated secretion, and humanized knock-in alleles rescue the hypertensive phenotype.","evidence":"VGF KO and humanized knock-in mice, electron microscopy, catecholamine measurements, blood pressure telemetry, VGF overexpression in NIH 3T3 cells","pmids":["24497580"],"confidence":"High","gaps":["Mechanism by which VGF nucleates granule formation not elucidated","Contribution of individual VGF peptides vs. full-length protein to granule biogenesis not separated"]},{"year":2014,"claim":"Endogenous TLQP-21 was validated as a spinal pain mediator: immunoneutralization with intrathecal anti-TLQP-21 antibody blocked tactile and thermal hypersensitivity in both inflammatory and neuropathic pain models, acting through p38 and COX/LOX pathways.","evidence":"Intrathecal antibody administration, von Frey and thermal assays, pharmacological inhibitors in CFA and spared nerve injury models","pmids":["24657450"],"confidence":"High","gaps":["Specific receptor(s) mediating spinal TLQP-21 pro-nociceptive effect not definitively assigned","Cell-type-specific contribution (microglia vs. neurons) in spinal cord not fully resolved"]},{"year":2015,"claim":"A VGF-BDNF positive feedback loop for memory was established: fear training induces hippocampal TLQP-62 secretion, which activates TrkB and CREB; sequestering TLQP-62 after training impairs memory, and BDNF rescue restores it, placing VGF upstream and downstream of BDNF signaling.","evidence":"In vivo fear conditioning, intra-hippocampal antibody infusion, TrkB phosphorylation in slices, VGF KO and BDNF rescue, Rac1/cofilin/synapsin pathway analysis","pmids":["26180209"],"confidence":"High","gaps":["Direct receptor for TLQP-62 still unidentified","How TLQP-62 triggers BDNF release mechanistically unknown"]},{"year":2017,"claim":"VGF was shown to be essential for insulin secretory granule biogenesis: beta-cell-specific VGF KO profoundly impairs stimulus-coupled insulin secretion by disrupting cargo exit from the trans-Golgi network, proinsulin processing, and granule replenishment.","evidence":"Conditional KO (floxed VGF × beta-cell Cre), islet secretion assays, electron microscopy, TGN trafficking analysis","pmids":["28877479"],"confidence":"High","gaps":["Molecular partners mediating VGF's role at TGN not identified","Whether VGF's granin function vs. its peptide products drive granule biogenesis not resolved"]},{"year":2017,"claim":"Region-specific roles of VGF in mood regulation were mapped: dorsal hippocampal VGF is antidepressant while nucleus accumbens VGF is pro-depressant; ketamine's antidepressant action requires VGF and signals through AMPA receptors and mTOR downstream of TLQP-62.","evidence":"AAV-Cre regional KO/overexpression in floxed VGF mice, social defeat and forced swim tests, rapamycin and NBQX pharmacology","pmids":["29158577"],"confidence":"High","gaps":["Cell-type identity of VGF neurons mediating antidepressant vs. pro-depressant effects not fully resolved","Whether TLQP-62 is the sole mediator in each region not established"]},{"year":2020,"claim":"TLQP-21's microglial actions were dissected across two receptors: C3aR1 mediates phagocytosis and chemotaxis (validated by C3aR1-KO transcriptomics), while C1qBP mediates inhibition of purinergic signaling—and ICV TLQP-21 reduces amyloid pathology in 5xFAD Alzheimer mice.","evidence":"C3aR1-null microglia RNA-seq, phagocytosis/migration assays, patch clamp in brain slices, C1qBP antagonists, ICV osmotic pump delivery in 5xFAD mice","pmids":["31924226","32060170"],"confidence":"High","gaps":["Mechanism of amyloid clearance (direct phagocytosis vs. indirect neuroprotection) not fully resolved","Human genetic evidence linking VGF to Alzheimer risk is associative, not causal"]},{"year":2021,"claim":"An mTOR-dependent translational autoregulatory loop was discovered: TLQP-62 or fear memory training rapidly increases VGF protein via mTOR-dependent polysome loading without changing mRNA; the 3′UTR represses translation, and mice with truncated 3′UTR have enhanced VGF protein, improved memory, and reduced depression-like behavior.","evidence":"Polysome profiling, 3′UTR luciferase reporters, Vgf 3′UTR-truncation knock-in mice, rapamycin, behavioral testing","pmids":["34238925"],"confidence":"High","gaps":["RNA-binding proteins or miRNAs mediating 3′UTR repression not identified","Whether this translational control operates in non-neuronal VGF-expressing cells unknown"]},{"year":null,"claim":"Key unresolved questions include: the direct receptor for TLQP-62 has not been identified; structural details of TLQP-21 binding to C3aR1 and C1qBP are lacking; the molecular mechanism by which full-length VGF promotes dense-core vesicle biogenesis at the trans-Golgi network remains unknown; and whether VGF peptides vs. the intact precursor protein mediate granule formation has not been separated.","evidence":"","pmids":[],"confidence":"High","gaps":["TLQP-62 receptor identity unknown","No structural model for TLQP-21–receptor complexes","Granule biogenesis mechanism at molecular level uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[12,16,17,18,19,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[21,23]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,11,21,36]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,12,15,16,22]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,8,11,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[18,19,25,26]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13,22,24,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,25,26]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,9,12,16]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,21,23]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,4,5,10]}],"complexes":[],"partners":["C3AR1","C1QBP","PCSK1","PCSK2","CREB1","ASCL1","TCF12","EP300"],"other_free_text":[]},"mechanistic_narrative":"VGF is a neurotrophin- and activity-regulated secreted neuropeptide precursor that is proteolytically processed by prohormone convertases PC1/3 and PC2 into bioactive C-terminal peptides (TLQP-21, TLQP-62, AQEE-30, LQEQ-19, NERPs) released from large dense core vesicles via the regulated secretory pathway [PMID:7595538, PMID:12065665, PMID:16221685]. Transcription of VGF is controlled by a CREB/CRE-dependent promoter element cooperating with Ras/NGFI-A and neuron-specific bHLH (MASH1/HEB-p300) complexes, while its translation is regulated post-transcriptionally through an mTOR-dependent mechanism repressed by the 3′UTR [PMID:1377233, PMID:8756618, PMID:11755530, PMID:34238925]. VGF-derived peptides signal through the G protein-coupled receptor C3aR1 and the receptor gC1qR/C1qBP to modulate energy homeostasis via sympathoadrenal activation of adipose tissue, hippocampal synaptic plasticity and memory consolidation through a BDNF-TrkB positive feedback loop, microglial phagocytosis and motility, spinal nociceptive signaling via p38 MAPK in microglia, and insulin granule biogenesis and glucose-stimulated insulin secretion in pancreatic beta cells [PMID:23940034, PMID:24106277, PMID:10433265, PMID:18815270, PMID:22768837, PMID:28877479, PMID:19846725, PMID:31924226]. VGF additionally promotes oligodendrogenesis, neural progenitor proliferation, and exerts brain region-specific antidepressant or pro-depressant effects—with ketamine's antidepressant action requiring VGF expression and AMPA receptor/mTOR signaling downstream of TLQP-62 [PMID:27732860, PMID:24747217, PMID:29158577, PMID:30504797]."},"prefetch_data":{"uniprot":{"accession":"O15240","full_name":"Neurosecretory protein VGF","aliases":[],"length_aa":615,"mass_kda":67.3,"function":"Secreted polyprotein that is packaged and proteolytically processed by prohormone convertases PCSK1 and PCSK2 in a cell-type-specific manner (By similarity). VGF and peptides derived from its processing play many roles in neurogenesis and neuroplasticity associated with learning, memory, depression and chronic pain (By similarity) Plays a role in the control of body fluid homeostasis by regulating vasopressin release. Suppresses presynaptic glutamatergic neurons connected to vasopressin neurons Plays a role in the control of body fluid homeostasis by regulating vasopressin release. Activates GABAergic interneurons which are inhibitory neurons of the nervous system and thereby suppresses presynaptic glutamatergic neurons (By similarity). Also stimulates feeding behavior in an orexin-dependent manner in the hypothalamus (By similarity). Functions as a positive regulator for the activation of orexin neurons resulting in elevated gastric acid secretion and gastric emptying (By similarity) Secreted multifunctional neuropeptide that binds to different cell receptors and thereby plays multiple physiological roles including modulation of energy expenditure, pain, response to stress, gastric regulation, glucose homeostasis as well as lipolysis (By similarity). Activates the G-protein-coupled receptor C3AR1 via a folding-upon-binding mechanism leading to enhanced lipolysis in adipocytes (By similarity). Interacts with C1QBP receptor in macrophages and microglia causing increased levels of intracellular calcium and hypersensitivity (By similarity) Plays a role in the regulation of memory formation and depression-related behaviors potentially by influencing synaptic plasticity and neurogenesis. Induces acute and transient activation of the NTRK2/TRKB receptor and subsequent CREB phosphorylation (By similarity). Also induces insulin secretion in insulinoma cells by increasing intracellular calcium mobilization (By similarity) Has bactericidal activity against M.luteus, and antifungal activity against P. Pastoris","subcellular_location":"Secreted; Cytoplasmic vesicle, secretory vesicle","url":"https://www.uniprot.org/uniprotkb/O15240/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VGF","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VGF","total_profiled":1310},"omim":[{"mim_id":"602563","title":"NK6 HOMEOBOX 1; NKX6-1","url":"https://www.omim.org/entry/602563"},{"mim_id":"602186","title":"VGF, NERVE GROWTH FACTOR-INDUCIBLE; VGF","url":"https://www.omim.org/entry/602186"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Golgi apparatus","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":143.5},{"tissue":"pituitary gland","ntpm":91.1}],"url":"https://www.proteinatlas.org/search/VGF"},"hgnc":{"alias_symbol":["SCG7","SgVII"],"prev_symbol":[]},"alphafold":{"accession":"O15240","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15240","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15240-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15240-F1-predicted_aligned_error_v6.png","plddt_mean":60.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VGF","jax_strain_url":"https://www.jax.org/strain/search?query=VGF"},"sequence":{"accession":"O15240","fasta_url":"https://rest.uniprot.org/uniprotkb/O15240.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15240/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15240"}},"corpus_meta":[{"pmid":"18059283","id":"PMC_18059283","title":"Antidepressant actions of the exercise-regulated gene VGF.","date":"2007","source":"Nature 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The promoter contains TATAA, CCAAT elements, GC boxes, and a consensus CRE-binding protein site.\",\n      \"method\": \"Northern/RNase protection analysis, promoter cloning and sequencing, transcription reporter assays in PC12 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — promoter characterization with multiple methods, replicated across labs\",\n      \"pmids\": [\"2017159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"NGF induces VGF gene expression at the transcriptional level through a consensus CRE embedded in a 14-bp palindrome immediately upstream of the transcription start site; mutation of this CRE eliminates induction by both NGF and cAMP. This element selectively responds to NGF/cAMP but not EGF, FGF, or PMA. The inducible transcription factor CREB binds this CRE.\",\n      \"method\": \"Promoter mutagenesis, transient transfection reporter assays, EMSA (CREB binding), pharmacological treatments in PC12 cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis plus EMSA plus functional transcription assay in same study\",\n      \"pmids\": [\"1377233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"VGF gene induction by NGF requires ongoing protein synthesis (transcription-dependent), is partly repressed in non-neuronal cells by a nuclear repressor, and a 110-bp promoter region contains both positive and negative regulatory elements. A 47-bp oligonucleotide within this region specifically binds nuclear proteins that differ between VGF-expressing and non-expressing cells.\",\n      \"method\": \"Transcriptional run-on, promoter-reporter transfection, EMSA with cell-type-specific nuclear extracts, protein synthesis inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods establishing transcriptional mechanism\",\n      \"pmids\": [\"1570299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"VGF precursor undergoes tissue-specific proteolytic processing in a post-ER compartment to produce low-molecular-weight species (~20, 18, 10 kDa). These processed forms are enriched in secretory vesicles and preferentially secreted upon membrane depolarization, indicating regulated release from dense core vesicles.\",\n      \"method\": \"Immunoblotting with N- and C-terminal antisera, subcellular fractionation, depolarization-induced secretion assays in cerebellar granule cells and PC12 cells\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — fractionation plus functional secretion assay, multiple cell types\",\n      \"pmids\": [\"7595538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"VGF transcriptional induction by NGF is mediated through a Ras-dependent signaling pathway. Three promoter elements are required: a CRE (binding ATF-1, ATF-2, CREB), a novel CCAAT element, and a G(S)G element between the TATA box and transcription start site that binds the NGF/Ras-induced transcription factor NGFI-A. All three are necessary but no single element is sufficient.\",\n      \"method\": \"Chimeric vgf/beta-globin reporter gene transfection, dominant-interfering and activated Ras mutants, TrkA mutants, promoter deletional/mutational analysis, EMSA\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis plus genetic (Ras pathway) epistasis in same study\",\n      \"pmids\": [\"8756618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"VGF promoter regulation involves cooperative binding of an E-box (binding HTF4/HEB E-protein as part of a multiprotein complex) and a CRE; the E-box acts as a repressor in non-neuronal (NIH 3T3) cells but as a stimulator in NGF-responsive PC12 cells. A neuro-specific bHLH transcription factor (MASH1) participates in neurotrophin-dependent transcription via the CCAAT motif.\",\n      \"method\": \"EMSA, expression cDNA cloning, reporter gene transfection, mutational analysis of E-box and CRE\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical isolation of binding factors plus mutagenesis in same study\",\n      \"pmids\": [\"9032251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"VGF knockout mice are lean, hypermetabolic, hyperactive, and infertile with markedly reduced leptin levels, fat stores, and altered hypothalamic POMC, NPY, and AGRP expression, establishing a non-redundant role for VGF in energy homeostasis. VGF mRNA is induced in hypothalamic arcuate nuclei upon fasting.\",\n      \"method\": \"Targeted gene deletion (knockout mice), metabolic phenotyping, in situ hybridization\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean germline KO with defined multi-system metabolic phenotype, highly cited foundational paper\",\n      \"pmids\": [\"10433265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"VGF is expressed in insulin-secreting INS-1 beta cells, where it is processed in a post-ER compartment and its peptides are released via a regulated secretory pathway upon stimulation with glucose, cAMP, or PMA. VGF mRNA in INS-1 cells is transcriptionally upregulated by increased intracellular cAMP but not by glucose or NGF.\",\n      \"method\": \"RT-PCR, metabolic labeling, immunoprecipitation, secretion assays in INS-1 cells\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (transcription + secretion) in same study\",\n      \"pmids\": [\"10433233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PC1/3 and PC2 prohormone convertases process the VGF precursor: both generate VGF20 (a ~20 kDa C-terminal fragment), while VGF10 is preferentially produced by PC1/3. The KRKRKK(488) motif is the target cleavage site generating VGF20 (identified by site-directed mutagenesis); VGF10 results from cleavage at RPR(555). Two additional novel VGF peptides were identified in rat brain by MALDI-ToF MS and Edman degradation.\",\n      \"method\": \"Ectopic expression of PC1/3 or PC2 in GH3 cells, site-directed mutagenesis of VGF cleavage sites, MALDI-ToF MS, Edman degradation\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution (ectopic PC expression) plus mutagenesis plus MS structural identification\",\n      \"pmids\": [\"12065665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"VGF and POMC are co-expressed in lateral arcuate neurons in fed state; VGF expression is induced in medial arcuate NPY neurons after fasting. VGF mRNA induction in fasted mice is inhibited by exogenous leptin, and is elevated in leptin-deficient ob/ob and db/db mice. VGF deficiency completely blocks obesity in agouti (Ay/a) mice but only attenuates weight gain in ob/ob mice, placing VGF downstream of melanocortin 4 receptors in autonomic outflow pathways.\",\n      \"method\": \"Double-label in situ hybridization, genetic epistasis (VGF KO × Ay/a, ob/ob, db/db crosses), leptin injection, gold thioglucose and diet-induced obesity models\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis in multiple genetic models with pathway placement\",\n      \"pmids\": [\"12177191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NGF-dependent and tissue-specific transcription of vgf is regulated by a CREB-p300 complex and a bHLH factor interaction. In non-neuronal cells, HEB (ubiquitous bHLH) and p300 form a repressor complex at the promoter. In neuronal cells, neurotrophin-dependent transcription is mediated by a distinct complex containing CREB, MASH1 (neuro-specific bHLH), and p300 bound to the CCAAT motif.\",\n      \"method\": \"Co-immunoprecipitation, EMSA, chromatin immunoprecipitation, reporter gene transfection, dominant-negative approaches\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — protein complex identification plus functional reporter assays\",\n      \"pmids\": [\"11755530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VGF sorting into the regulated secretory pathway (large dense core vesicles, LDCVs) requires a compact C-terminal alpha-helix and an embedded 564RRR566 prohormone convertase cleavage site. Mutation of 564RRR566 blocks regulated secretion; mutation of adjacent 567HFHH570 also blocks regulated release. Inhibition of PC cleavage by membrane-permeable chloromethyl ketone (decanoyl-RVKR-CMK) blocks regulated VGF secretion.\",\n      \"method\": \"Deletional and site-directed mutagenesis of VGF, confocal microscopy, subcellular fractionation, pharmacological PC inhibition in PC12 and INS-1 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis plus cell biology of trafficking with multiple cell types\",\n      \"pmids\": [\"16221685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The VGF-derived peptide TLQP-21 (identified in rat brain by immunoprecipitation/LC-MS/MS) increases resting energy expenditure and rectal temperature upon chronic ICV injection in mice, preventing diet-induced obesity. TLQP-21 acts by stimulating autonomic activation of the adrenal medulla, upregulating brown adipose tissue beta2-AR and white adipose tissue PPAR-delta, beta3-AR, and UCP1 mRNAs, independently of thyroid hormones or locomotor activity.\",\n      \"method\": \"LC-MS/MS peptide identification, chronic ICV injection, indirect calorimetry, gene expression (RT-PCR), hormonal measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — endogenous peptide identified by MS, functional mechanism characterized by multiple molecular readouts\",\n      \"pmids\": [\"16983076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The VGF C-terminal peptide TLQP-62 induces transient potentiation in rat hippocampal slices through a mechanism blocked by the BDNF scavenger TrkB-Fc, Trk kinase inhibitor K252a, and tPA inhibitor tPASTOP, but not by NMDA receptor antagonist APV or anti-p75NTR. VGF knockout mice cannot undergo hippocampal LTD and show impaired spatial learning and contextual fear conditioning.\",\n      \"method\": \"Electrophysiology in hippocampal slices (LTP/LTD), pharmacological blockade with specific inhibitors, VGF KO behavioral testing (Morris water maze, fear conditioning)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection of signaling pathway plus KO phenotype in same study\",\n      \"pmids\": [\"18815270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"VGF-derived peptides AQEE-30 and LQEQ-19 evoke dose-dependent thermal hyperalgesia upon intrathecal injection via activation of p38 MAP kinase. LQEQ-19 induces p38 phosphorylation in spinal microglia in vivo and in BV-2 microglial cells in vitro. VGF protein levels are rapidly upregulated in dorsal root ganglion neurons after nerve injury and hindpaw inflammation.\",\n      \"method\": \"Intrathecal peptide injection, thermal hyperalgesia assays, p38 immunostaining/phospho-western, proteomics of DRG neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo and in vitro assays linking VGF peptides to p38-dependent nociceptive signaling\",\n      \"pmids\": [\"19846725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NERP-1 and NERP-2, novel bioactive peptides derived from VGF, co-localize with vasopressin in storage granules of paraventricular and supraoptic hypothalamic nuclei. Administration of NERPs suppresses vasopressin release from hypothalamus and pituitary induced by hypertonic saline or angiotensin II.\",\n      \"method\": \"Immunohistochemistry/co-localization, in vivo and ex vivo vasopressin secretion assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-localization plus in vivo functional secretion assay, single lab\",\n      \"pmids\": [\"19194657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TLQP-21 promotes lipolysis in murine white adipose tissue (WAT) via a saturable receptor-binding mechanism that requires activation of noradrenaline/beta-adrenergic receptor pathways. VGF immunoreactivity is present in sympathetic nerve fibers innervating WAT but not in adipocytes. TLQP-21 binding capacity is higher in WAT than other tissues and is upregulated in obese mice.\",\n      \"method\": \"Receptor binding assays (saturation binding), lipolysis assays in primary adipocytes, immunohistochemistry, in vivo injection in obesity models\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor binding plus mechanistic pharmacology plus in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"21880012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nkx6.1 strongly upregulates VGF in rat islets, and VGF is necessary and sufficient for Nkx6.1-mediated enhancement of glucose-stimulated insulin secretion (GSIS). The VGF-derived peptide TLQP-21 potentiates GSIS in rat and human islets and improves glucose tolerance in vivo. Chronic TLQP-21 injection in prediabetic ZDF rats preserves islet mass. TLQP-21 prevents islet apoptosis by a GLP-1/GIP/VIP receptor-independent pathway similar to that of GLP-1.\",\n      \"method\": \"Overexpression/knockdown of VGF in rat islets, GSIS assays, receptor antagonist studies, in vivo ZDF rat treatment, apoptosis assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function plus mechanistic pharmacology in islets and in vivo\",\n      \"pmids\": [\"22768837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C3a receptor-1 (C3AR1) is a G protein-coupled receptor target for the VGF-derived peptide TLQP-21 in rodent cells. Identified by unbiased genome-wide transcriptome sequencing of responsive CHO-K1 cells, confirmed by siRNA knockdown and receptor antagonists. TLQP-21 signaling through C3AR1 is pertussis toxin-sensitive (consistent with Gi/o coupling) and directs migration of mouse RAW264.7 macrophages.\",\n      \"method\": \"Unbiased RNA-seq-based receptor deorphanization, siRNA knockdown, receptor antagonists, pertussis toxin, cell migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased screen plus genetic (siRNA) and pharmacological validation, multiple functional readouts\",\n      \"pmids\": [\"23940034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"gC1qR (globular heads of the C1q receptor) is a receptor for the VGF-derived peptide TLQP-21, identified by chemical cross-linking combined with mass spectrometry. TLQP-21 causes increased intracellular Ca2+ in rat macrophages and microglia via gC1qR. TLQP-21-stimulated macrophages cause mechanical hypersensitivity when inoculated into rat hind paw; gC1qR-neutralizing antibody attenuates neuropathic pain in partial sciatic nerve ligation.\",\n      \"method\": \"Chemical cross-linking/mass spectrometry, siRNA knockdown, neutralizing antibodies, intracellular Ca2+ imaging, in vivo pain model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — chemical cross-linking/MS receptor identification plus genetic and pharmacological validation plus in vivo pain model\",\n      \"pmids\": [\"24106277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TLQP-21 induces thermal hyperalgesia via p38 MAP kinase and is inhibited by cyclooxygenase and lipoxygenase inhibitors. Immunoneutralization of endogenous TLQP-21 by intrathecal anti-TLQP-21 antibody inhibits tactile hypersensitivity and thermal hyperalgesia in CFA-induced inflammation and spared nerve injury neuropathic pain models, demonstrating that endogenous TLQP-21 contributes to spinal pain sensitization.\",\n      \"method\": \"Intrathecal peptide/antibody administration, von Frey and thermal withdrawal assays, pharmacological inhibitors (p38, COX, LOX) in CFA and SNI mouse models\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — immunoneutralization of endogenous peptide plus pharmacological pathway dissection in two in vivo models\",\n      \"pmids\": [\"24657450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The granin VGF promotes biogenesis of large dense core vesicles (LDCVs) in the adrenal medulla. VGF knockout mice have decreased LDCV size in noradrenergic chromaffin cells, increased adrenal norepinephrine and epinephrine content, elevated plasma epinephrine, decreased adrenal chromogranin B, and hypertension. Expression of exogenous VGF in NIH 3T3 fibroblasts generates LDCV-like structures with depolarization-induced secretion. Knock-in of human VGF1-615 rescues the hypertensive phenotype; knock-in of truncated VGF1-524 (lacking TLQP-21) only partially rescues it. Acute and chronic TLQP-21 administration decreases blood pressure.\",\n      \"method\": \"Germline VGF KO and humanized knock-in mice, electron microscopy of adrenal chromaffin cells, catecholamine measurements, blood pressure telemetry, VGF overexpression in NIH 3T3 fibroblasts, peptide administration\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — reconstitution in fibroblasts + genetic rescue with knock-in alleles + ultrastructural analysis\",\n      \"pmids\": [\"24497580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VGF expression and secretion of C-terminal peptide TLQP-62 in hippocampus are transiently induced after fear memory training. Sequestering TLQP-62 after training impairs memory formation. TLQP-62 induces acute TrkB receptor phosphorylation and subsequent CREB phosphorylation in hippocampal slices. TLQP-62's memory-enhancing effect is rescued by BDNF-TrkB signaling activation and is VGF-dependent (germline or antibody-sequestration experiments). VGF-deficient mice show impaired Rac1 induction and reduced cofilin/synapsin phosphorylation after learning.\",\n      \"method\": \"In vivo fear conditioning, intra-hippocampal antibody infusion, hippocampal slice TrkB phosphorylation assays, VGF KO mice, BDNF rescue experiments, signaling pathway analysis (Rac1, cofilin, synapsin)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (KO, antibody sequestration, pathway rescue, electrophysiology) in same study\",\n      \"pmids\": [\"26180209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VGF regulates insulin secretory granule biogenesis in pancreatic beta cells. Conditional VGF knockout in islets and beta-cell-specific knockout mice show profound decreases in stimulus-coupled insulin secretion. VGF is required for efficient exit of granule cargo from the trans-Golgi network, for proinsulin processing, and for replenishment of insulin granule stores after nutrient stimulation.\",\n      \"method\": \"Conditional KO (floxed VGF mice + Cre), islet secretion assays, electron microscopy of secretory granules, proinsulin processing analysis, trans-Golgi network trafficking assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — conditional KO with defined cellular granule biogenesis phenotype plus trafficking assays\",\n      \"pmids\": [\"28877479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VGF regulates depression-like behavior in dorsal hippocampus (dHc) and nucleus accumbens (NAc) in opposite directions: dHc VGF ablation produces pro-depressant behavior and dHc VGF overexpression produces antidepressant behavior; NAc VGF ablation is antidepressant and overexpression is pro-depressant. The antidepressant efficacy of ketamine requires VGF expression and is associated with rapid VGF translation. TLQP-62 antidepressant effects in dHc require AMPA receptor and mTOR signaling (blocked by NBQX and rapamycin). Conditional pan-neuronal (but not forebrain) VGF ablation increases stress susceptibility, indicating neuronal (partially inhibitory interneuron) VGF regulates depression.\",\n      \"method\": \"AAV-Cre conditional KO and overexpression in floxed VGF mice (region-specific), germline VGF heterozygous mice, social defeat stress, forced swim test, AMPA/mTOR pharmacological inhibitors, Synapsin-Cre and αCaMKII-Cre crosses\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional region-specific KO/OE with multiple genetic and pharmacological controls establishing pathway placement\",\n      \"pmids\": [\"29158577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TLQP-21 increases motility and phagocytic capacity in murine microglia via C3aR1 signaling. C3aR1-null primary microglia have impaired basal phagocytic function; TLQP-21 and C3a super agonist induce overlapping transcriptomic changes (migration/proliferation genes) in wild-type but not C3aR1-null microglia. ICV TLQP-21 in 5xFAD mice reduces amyloid plaques, associated dystrophic neurites, and restores Alzheimer-associated microglial gene expression. Human TLQP-21 activates human microglia similarly to mouse TLQP-21.\",\n      \"method\": \"Phagocytosis/migration assays, RNA-seq of primary microglia (WT vs. C3aR1-null), osmotic pump ICV delivery in 5xFAD mice, immunohistochemistry for amyloid plaques, human HMC3 microglial cell line assays\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (C3aR1 KO) and pharmacological validation, transcriptomics, and in vivo rescue in AD model\",\n      \"pmids\": [\"31924226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TLQP-21 impairs metabotropic purinergic (P2Y) signaling in microglia in acute brain slices, attenuating ATP-induced K+ conductance, UDP-stimulated phagocytosis, and ATP-dependent process outgrowth toward injury. These impairments are reversed by blocking C1qBP but not C3aR1. In cultured microglia (which express both receptors), TLQP-21 additionally evokes Ca2+ transients, membrane currents, and chemotaxis via C3aR1, demonstrating dual receptor-dependent effects.\",\n      \"method\": \"Whole-cell patch clamp in brain slices, phagocytosis assays, laser lesion-induced process outgrowth imaging, Ca2+ imaging, C1qBP and C3aR1 antagonists, primary microglia from C3aR1-null mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology plus Ca2+ imaging plus genetic (C3aR1-null) and pharmacological (C1qBP antagonist) dissection in same study\",\n      \"pmids\": [\"32060170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SOX9 drives injury-induced transcriptional upregulation of VGF in renal tubular epithelial cells (RTECs). RTEC-specific Vgf gene ablation exacerbates ischemia-, cisplatin-, and rhabdomyolysis-induced acute kidney injury in vivo and cisplatin-induced RTEC death in vitro. Aggravation of cisplatin injury by Vgf ablation is partly reversed by exogenous TLQP-21 peptide.\",\n      \"method\": \"Renal transcriptome profiling in three AKI mouse models, RTEC-specific conditional KO, in vitro cell death assays, SOX9 ChIP/reporter assays, TLQP-21 rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO in three AKI models plus upstream transcription factor identification and peptide rescue\",\n      \"pmids\": [\"32887795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TLQP-62 or contextual fear memory training acutely increases translation of VGF and other granin proteins (CgB, Scg2) via mTOR-dependent signaling without measurable increases in mRNA, constituting a transcription-independent autofeedback mechanism. The 3'UTR of Vgf mRNA represses VGF translation (validated by luciferase reporter). Mice with truncated endogenous Vgf 3'UTR show substantially increased VGF protein, enhanced memory performance, and reduced anxiety/depression-like behaviors.\",\n      \"method\": \"Polysome/translation assays, luciferase 3'UTR reporter assays, Vgf 3'UTR-truncation knock-in mice, mTOR inhibition (rapamycin), fear conditioning behavioral assays\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reporter mutagenesis plus knock-in genetic model plus pharmacological inhibition establishing translational mechanism\",\n      \"pmids\": [\"34238925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The VGF-derived peptide TLQP-21 promotes survival of rat cerebellar granule cells (CGCs) against serum/potassium deprivation-induced apoptosis in a dose- and time-dependent manner. Neuroprotection is associated with activation of ERK1/2, Akt (serine/threonine kinase), and JNK phosphorylation, decreased PKC phosphorylation, and increased intracellular Ca2+ in ~60% of neurons.\",\n      \"method\": \"Cell viability assays, DNA fragmentation (apoptosis), western blot for kinase phosphorylation, fura-2AM Ca2+ imaging in primary CGC cultures\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pharmacological and biochemical readouts but no receptor identification or genetic validation\",\n      \"pmids\": [\"18173805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TLQP-62 induces proliferation of early-phase (Type 2a nestin+) neural progenitor cells in the adult hippocampus via NMDA receptor- and mGluR5-dependent glutamate signaling, activating CaMKII and PKD, respectively. TLQP-62 also gradually activates TrkB (BDNF receptor), and TrkB signaling is required for TLQP-62-induced NPC proliferation.\",\n      \"method\": \"Nestin-GFP reporter mice, BrdU/thymidine incorporation, NPC proliferation assays in vitro (cell line and primary progenitors), pharmacological NMDA/mGluR5/CaMKII/PKD inhibitors, Cyclin D qPCR, TrkB inhibitors\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological pathway dissections plus in vivo reporter mouse in same study\",\n      \"pmids\": [\"24747217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Voluntary running induces VGF expression in the brain, which promotes oligodendrogenesis in the cerebellum of Snf2h conditional knockout ataxic mice, prolonging survival. VGF neuropeptides promote oligodendrogenesis in vitro, and adenoviral VGF overexpression in vivo rescues survival without requiring exercise.\",\n      \"method\": \"Conditional Snf2h KO mice, voluntary wheel running, VGF adenoviral overexpression, oligodendrocyte lineage cell counts, in vitro oligodendrogenesis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue (adenoviral VGF) phenocopies exercise effect plus in vitro mechanistic validation\",\n      \"pmids\": [\"27732860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TLQP-21 induces contraction of rat forestomach smooth muscle by releasing prostaglandins PGE2 and PGF2a from the mucosal layer, blocked by indomethacin and selective COX-1/COX-2 inhibitors. ICV TLQP-21 decreases gastric emptying by ~40% via central PG release. VGF immunoreactivity is present in gastric neuronal cells.\",\n      \"method\": \"Isolated smooth muscle preparation, in vitro contraction assays, pharmacological inhibitors (indomethacin, COX-1/2), in vivo ICV injection, gastric emptying measurement, immunostaining\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro pharmacological mechanism plus in vivo, but single lab\",\n      \"pmids\": [\"19466987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VGF and TLQP-62 in ventromedial prefrontal cortex (vmPFC) regulate stress susceptibility and antidepressant response to ketamine. TLQP-62 antidepressant-like effects in vmPFC require BDNF expression and calcium mobilization (blocked by xestospongin C, an IP3 receptor inhibitor, and SKF96365, a TRPC/store-operated channel inhibitor), revealing a calcium-dependent signaling mechanism downstream of TLQP-62/BDNF.\",\n      \"method\": \"AAV-Cre conditional VGF KO and overexpression in floxed VGF mice (vmPFC), intra-vmPFC TLQP-62 infusion, Bdnf conditional KO, pharmacological Ca2+ pathway inhibitors, chronic restraint stress, subchronic variable stress\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — region-specific conditional genetics plus pharmacological dissection of Ca2+ mechanism in same study\",\n      \"pmids\": [\"30504797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"lncRNA H19 binds VGF protein (demonstrated by RNA pulldown and mass spectrometry) and promotes pancreatic neuroendocrine neoplasm (pNEN) cell proliferation, migration and invasion. VGF activated PI3K/AKT/CREB signaling; H19 activates this signaling pathway via VGF, and VGF knockdown reduces these oncogenic phenotypes.\",\n      \"method\": \"RNA pulldown/mass spectrometry, RIP, siRNA knockdown, in vitro proliferation/migration/invasion assays, RNA-seq, in vivo xenograft\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RNA pulldown/MS identifying lncRNA-VGF interaction plus functional knockdown, single lab\",\n      \"pmids\": [\"31117050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"VGF immunoreactivity in the hypothalamus co-localizes with vasopressin or vasoactive intestinal polypeptide in SCN neurons, and with oxytocin or vasopressin in paraventricular and supraoptic nuclei. Ultrastructural studies show VGF immunoreactivity in presynaptic boutons in SCN and in axons of the neurohypophysis, consistent with a secretory neuropeptide role.\",\n      \"method\": \"Immunocytochemistry with two non-overlapping antisera, colchicine axonal transport blockade, co-localization by immunofluorescence, electron microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple antisera, ultrastructural localization, co-localization in defined cell types, highly cited\",\n      \"pmids\": [\"2556505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"VGF is localized to a subpopulation of large dense core vesicles in PC12 cells (by electron microscopy). In developing hippocampal neurons, VGF-containing vesicles are present from earliest developmental stages and are particularly abundant in GABAergic neurons; VGF becomes restricted to axons after dendrites mature (associated with synaptogenesis, not axonal polarization). VGF-containing and synaptophysin-containing vesicles are distinct and differentially distributed.\",\n      \"method\": \"Electron microscopy immunolabeling in PC12 cells, immunofluorescence co-localization in hippocampal neurons, developmental staging\",\n      \"journal\": \"Brain research. Developmental brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ultrastructural localization plus developmental co-localization, single lab\",\n      \"pmids\": [\"8922684\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VGF is a neurotrophin (NGF/BDNF)-inducible, activity-regulated secreted neuropeptide precursor that is transcriptionally controlled via a CREB/CRE-dependent promoter (additionally regulated by Ras/NGFI-A, HEB/MASH1-p300 bHLH complexes), sorted into large dense core vesicles through a C-terminal RRR prohormone convertase site, proteolytically processed by PC1/3 and PC2, and secreted in a regulated manner; its bioactive C-terminal peptides (especially TLQP-21 and TLQP-62) act on G protein-coupled receptors (C3aR1, gC1qR/C1qBP) to modulate energy balance and lipid metabolism through sympathoadrenal pathways, promote hippocampal synaptic plasticity and memory consolidation via a BDNF-TrkB positive feedback loop requiring mTOR-dependent translation and AMPA receptor insertion, regulate microglial phagocytosis and motility through C3aR1/purinergic signaling, control insulin granule biogenesis and secretion in beta cells, and exert pro-nociceptive effects in the spinal cord through p38 MAP kinase activation in microglia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"VGF is a neurotrophin- and activity-regulated secreted neuropeptide precursor that is proteolytically processed by prohormone convertases PC1/3 and PC2 into bioactive C-terminal peptides (TLQP-21, TLQP-62, AQEE-30, LQEQ-19, NERPs) released from large dense core vesicles via the regulated secretory pathway [PMID:7595538, PMID:12065665, PMID:16221685]. Transcription of VGF is controlled by a CREB/CRE-dependent promoter element cooperating with Ras/NGFI-A and neuron-specific bHLH (MASH1/HEB-p300) complexes, while its translation is regulated post-transcriptionally through an mTOR-dependent mechanism repressed by the 3′UTR [PMID:1377233, PMID:8756618, PMID:11755530, PMID:34238925]. VGF-derived peptides signal through the G protein-coupled receptor C3aR1 and the receptor gC1qR/C1qBP to modulate energy homeostasis via sympathoadrenal activation of adipose tissue, hippocampal synaptic plasticity and memory consolidation through a BDNF-TrkB positive feedback loop, microglial phagocytosis and motility, spinal nociceptive signaling via p38 MAPK in microglia, and insulin granule biogenesis and glucose-stimulated insulin secretion in pancreatic beta cells [PMID:23940034, PMID:24106277, PMID:10433265, PMID:18815270, PMID:22768837, PMID:28877479, PMID:19846725, PMID:31924226]. VGF additionally promotes oligodendrogenesis, neural progenitor proliferation, and exerts brain region-specific antidepressant or pro-depressant effects—with ketamine's antidepressant action requiring VGF expression and AMPA receptor/mTOR signaling downstream of TLQP-62 [PMID:27732860, PMID:24747217, PMID:29158577, PMID:30504797].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Before VGF's molecular function was known, ultrastructural co-localization with vasopressin and oxytocin in hypothalamic neurosecretory terminals established it as a candidate secreted neuropeptide rather than an intracellular signaling protein.\",\n      \"evidence\": \"Immunocytochemistry with two antisera plus electron microscopy in rat hypothalamus\",\n      \"pmids\": [\"2556505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No identification of processed peptides\", \"Secretion stimulus not tested\", \"Function of VGF in these neurons unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defining how neurotrophin signals reach the VGF locus, studies showed that a CRE immediately upstream of the transcription start site is both necessary and sufficient for NGF/cAMP-mediated induction, with CREB binding this element—establishing VGF as a direct CREB target gene.\",\n      \"evidence\": \"Promoter mutagenesis, EMSA for CREB binding, and transcription reporter assays in PC12 cells\",\n      \"pmids\": [\"2017159\", \"1377233\", \"1570299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-level regulation not addressed\", \"In vivo relevance of CRE not tested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The question of how multiple cis-elements cooperate was resolved by showing that NGF-induced VGF transcription requires three elements—CRE, CCAAT, and a G(S)G element binding the Ras-induced factor NGFI-A—none sufficient alone, placing VGF downstream of the Ras-MAPK cascade.\",\n      \"evidence\": \"Chimeric reporter mutagenesis, dominant-negative Ras, TrkA mutants, EMSA in PC12 cells\",\n      \"pmids\": [\"8756618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each element in vivo undetermined\", \"Post-translational modifications of NGFI-A at VGF promoter not characterized\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Cell-type restriction of VGF expression was explained by the finding that the E-box/CCAAT region recruits a repressive HEB complex in non-neuronal cells but a stimulatory MASH1-p300 complex in neuronal cells, later shown to involve CREB-p300 cooperation for neurotrophin-dependent activation.\",\n      \"evidence\": \"EMSA, expression cloning, reporter mutagenesis, co-immunoprecipitation, and ChIP\",\n      \"pmids\": [\"9032251\", \"11755530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epigenetic marks distinguishing repressor vs. activator states not mapped\", \"In vivo ChIP not performed\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"The question of whether VGF is a regulated secretory molecule was answered: VGF precursor undergoes tissue-specific post-ER cleavage into low-MW peptides enriched in secretory vesicles and preferentially released upon depolarization, confirming regulated dense-core vesicle secretion.\",\n      \"evidence\": \"Subcellular fractionation, immunoblotting with domain-specific antisera, depolarization-induced secretion in cerebellar granule and PC12 cells\",\n      \"pmids\": [\"7595538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Convertases responsible not yet identified\", \"Sorting signals not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The identity of VGF-processing enzymes was established: PC1/3 and PC2 cleave VGF at KRKRKK(488) and RPR(555) to generate the major C-terminal fragments VGF20 and VGF10, and novel brain peptides were structurally identified by mass spectrometry.\",\n      \"evidence\": \"Ectopic PC1/3 and PC2 expression in GH3 cells, site-directed mutagenesis, MALDI-ToF MS and Edman degradation of rat brain extracts\",\n      \"pmids\": [\"12065665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full peptidomic catalogue of VGF-derived peptides incomplete\", \"Tissue-specific differences in processing not fully mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The sorting mechanism was resolved: a C-terminal alpha-helix containing the 564RRR566 convertase site and adjacent 567HFHH570 residues are required for VGF entry into the regulated secretory pathway, linking prohormone processing to vesicular trafficking.\",\n      \"evidence\": \"Systematic mutagenesis, confocal imaging, subcellular fractionation, PC inhibitor in PC12 and INS-1 cells\",\n      \"pmids\": [\"16221685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chaperone or adaptor mediating recognition of this signal unknown\", \"Whether this mechanism generalizes to all tissues not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The first physiological role was established: VGF knockout mice are lean, hypermetabolic, hyperactive, and infertile, demonstrating a non-redundant requirement for VGF in energy homeostasis and reproduction.\",\n      \"evidence\": \"Germline VGF KO mice, metabolic phenotyping, in situ hybridization for hypothalamic neuropeptides\",\n      \"pmids\": [\"10433265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which VGF-derived peptide(s) mediate the metabolic phenotype unknown\", \"CNS vs. peripheral contributions not separated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"VGF was placed in the melanocortin pathway: genetic epistasis showed VGF deficiency blocks obesity in agouti (Ay/a) mice but only attenuates it in ob/ob mice, positioning VGF downstream of MC4R signaling in autonomic outflow circuits.\",\n      \"evidence\": \"Double-mutant crosses (VGF KO × Ay/a, ob/ob, db/db), in situ hybridization, leptin injection\",\n      \"pmids\": [\"12177191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MC4R-to-VGF transcriptional mechanism not shown\", \"Peripheral VGF contributions not excluded\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The first bioactive VGF peptide was functionally characterized: ICV TLQP-21 increases energy expenditure and prevents diet-induced obesity by stimulating sympathoadrenal activation of brown and white adipose tissue, independent of thyroid hormones.\",\n      \"evidence\": \"LC-MS/MS peptide identification from brain, chronic ICV infusion, indirect calorimetry, adipose gene expression, hormonal measurements in mice\",\n      \"pmids\": [\"16983076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor for TLQP-21 not yet identified\", \"Direct vs. indirect sympathetic activation not distinguished\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"TLQP-62 was shown to modulate hippocampal synaptic plasticity: it induces transient potentiation through a BDNF-TrkB-dependent mechanism (blocked by TrkB-Fc and tPA inhibition), and VGF KO mice lack hippocampal LTD and have impaired spatial learning and fear memory.\",\n      \"evidence\": \"Electrophysiology in hippocampal slices, pharmacological blockade, VGF KO behavioral testing\",\n      \"pmids\": [\"18815270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor for TLQP-62 not identified\", \"Whether TLQP-62 acts pre- or post-synaptically unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"VGF peptides were linked to pain signaling: AQEE-30 and LQEQ-19 evoke thermal hyperalgesia via p38 MAPK activation specifically in spinal microglia, and VGF is upregulated in DRG neurons after nerve injury, establishing VGF as a pro-nociceptive mediator.\",\n      \"evidence\": \"Intrathecal peptide injection, thermal assays, p38 immunostaining in spinal cord, DRG proteomics\",\n      \"pmids\": [\"19846725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating spinal microglial activation not identified\", \"Whether VGF peptides act as neuron-to-microglia signals in vivo not proven\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two receptors for TLQP-21 were identified: C3aR1 (a GPCR with Gi/o coupling) deorphanized by unbiased RNA-seq screening, and gC1qR/C1qBP identified by chemical cross-linking/MS, establishing the first direct receptor-ligand relationships for VGF-derived peptides.\",\n      \"evidence\": \"Genome-wide RNA-seq deorphanization, siRNA knockdown, chemical cross-linking/MS, receptor antagonists, Ca2+ imaging, macrophage migration, and in vivo pain models\",\n      \"pmids\": [\"23940034\", \"24106277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of C3aR1 vs. gC1qR in different tissues not systematically compared\", \"Structural basis of TLQP-21 binding to either receptor unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"VGF was shown to be a granin that drives dense-core vesicle biogenesis: VGF KO adrenal chromaffin cells have smaller LDCVs, while VGF expression in fibroblasts generates LDCV-like structures with regulated secretion, and humanized knock-in alleles rescue the hypertensive phenotype.\",\n      \"evidence\": \"VGF KO and humanized knock-in mice, electron microscopy, catecholamine measurements, blood pressure telemetry, VGF overexpression in NIH 3T3 cells\",\n      \"pmids\": [\"24497580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which VGF nucleates granule formation not elucidated\", \"Contribution of individual VGF peptides vs. full-length protein to granule biogenesis not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Endogenous TLQP-21 was validated as a spinal pain mediator: immunoneutralization with intrathecal anti-TLQP-21 antibody blocked tactile and thermal hypersensitivity in both inflammatory and neuropathic pain models, acting through p38 and COX/LOX pathways.\",\n      \"evidence\": \"Intrathecal antibody administration, von Frey and thermal assays, pharmacological inhibitors in CFA and spared nerve injury models\",\n      \"pmids\": [\"24657450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific receptor(s) mediating spinal TLQP-21 pro-nociceptive effect not definitively assigned\", \"Cell-type-specific contribution (microglia vs. neurons) in spinal cord not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A VGF-BDNF positive feedback loop for memory was established: fear training induces hippocampal TLQP-62 secretion, which activates TrkB and CREB; sequestering TLQP-62 after training impairs memory, and BDNF rescue restores it, placing VGF upstream and downstream of BDNF signaling.\",\n      \"evidence\": \"In vivo fear conditioning, intra-hippocampal antibody infusion, TrkB phosphorylation in slices, VGF KO and BDNF rescue, Rac1/cofilin/synapsin pathway analysis\",\n      \"pmids\": [\"26180209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor for TLQP-62 still unidentified\", \"How TLQP-62 triggers BDNF release mechanistically unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"VGF was shown to be essential for insulin secretory granule biogenesis: beta-cell-specific VGF KO profoundly impairs stimulus-coupled insulin secretion by disrupting cargo exit from the trans-Golgi network, proinsulin processing, and granule replenishment.\",\n      \"evidence\": \"Conditional KO (floxed VGF × beta-cell Cre), islet secretion assays, electron microscopy, TGN trafficking analysis\",\n      \"pmids\": [\"28877479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating VGF's role at TGN not identified\", \"Whether VGF's granin function vs. its peptide products drive granule biogenesis not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Region-specific roles of VGF in mood regulation were mapped: dorsal hippocampal VGF is antidepressant while nucleus accumbens VGF is pro-depressant; ketamine's antidepressant action requires VGF and signals through AMPA receptors and mTOR downstream of TLQP-62.\",\n      \"evidence\": \"AAV-Cre regional KO/overexpression in floxed VGF mice, social defeat and forced swim tests, rapamycin and NBQX pharmacology\",\n      \"pmids\": [\"29158577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type identity of VGF neurons mediating antidepressant vs. pro-depressant effects not fully resolved\", \"Whether TLQP-62 is the sole mediator in each region not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"TLQP-21's microglial actions were dissected across two receptors: C3aR1 mediates phagocytosis and chemotaxis (validated by C3aR1-KO transcriptomics), while C1qBP mediates inhibition of purinergic signaling—and ICV TLQP-21 reduces amyloid pathology in 5xFAD Alzheimer mice.\",\n      \"evidence\": \"C3aR1-null microglia RNA-seq, phagocytosis/migration assays, patch clamp in brain slices, C1qBP antagonists, ICV osmotic pump delivery in 5xFAD mice\",\n      \"pmids\": [\"31924226\", \"32060170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of amyloid clearance (direct phagocytosis vs. indirect neuroprotection) not fully resolved\", \"Human genetic evidence linking VGF to Alzheimer risk is associative, not causal\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An mTOR-dependent translational autoregulatory loop was discovered: TLQP-62 or fear memory training rapidly increases VGF protein via mTOR-dependent polysome loading without changing mRNA; the 3′UTR represses translation, and mice with truncated 3′UTR have enhanced VGF protein, improved memory, and reduced depression-like behavior.\",\n      \"evidence\": \"Polysome profiling, 3′UTR luciferase reporters, Vgf 3′UTR-truncation knock-in mice, rapamycin, behavioral testing\",\n      \"pmids\": [\"34238925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding proteins or miRNAs mediating 3′UTR repression not identified\", \"Whether this translational control operates in non-neuronal VGF-expressing cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the direct receptor for TLQP-62 has not been identified; structural details of TLQP-21 binding to C3aR1 and C1qBP are lacking; the molecular mechanism by which full-length VGF promotes dense-core vesicle biogenesis at the trans-Golgi network remains unknown; and whether VGF peptides vs. the intact precursor protein mediate granule formation has not been separated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TLQP-62 receptor identity unknown\", \"No structural model for TLQP-21–receptor complexes\", \"Granule biogenesis mechanism at molecular level uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [12, 16, 17, 18, 19, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [21, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 11, 21, 36]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 12, 15, 16, 22]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 8, 11, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [18, 19, 25, 26]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13, 22, 24, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 25, 26]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 9, 12, 16]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 21, 23]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 4, 5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"C3AR1\",\n      \"C1QBP\",\n      \"PCSK1\",\n      \"PCSK2\",\n      \"CREB1\",\n      \"ASCL1\",\n      \"TCF12\",\n      \"EP300\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}