{"gene":"NEGR1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1999,"finding":"NEGR1 (Kilon) is a GPI-anchored protein belonging to the IgLON immunoglobulin superfamily, containing three C2 domains and six putative glycosylation sites, localized to Triton-insoluble lipid raft membrane fractions in rat brain, with expression restricted to brain tissue.","method":"cDNA cloning, phosphatidylinositol-specific phospholipase C solubilization, Western blotting, peptide N-glycosidase F deglycosylation, immunostaining","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical characterization with multiple orthogonal methods (cloning, lipid raft fractionation, immunostaining), foundational characterization paper","pmids":["10075727"],"is_preprint":false},{"year":2003,"finding":"Kilon (NEGR1) and OBCAM interact both heterophilically and homophilically, as demonstrated by cross-linker and immunoprecipitation binding analysis; Kilon is localized mainly at postsynaptic sites of dendritic and somatic synapses in adult cerebral cortex and hippocampus, and is present predominantly in the Triton-insoluble fraction.","method":"Cross-linker treatment, immunoprecipitation, electron microscopic immunohistochemistry, Western blotting, subcellular fractionation","journal":"Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated by cross-linker/IP, ultrastructural localization by EM, multiple orthogonal methods in single study","pmids":["12617969"],"is_preprint":false},{"year":2005,"finding":"Neurotractin/kilon (NEGR1) promotes neurite outgrowth: in vitro stripe assays showed that neurotractin/kilon attracts hippocampal axons and astroglial neurotractin/kilon promotes neurite outgrowth; expression is upregulated on reactive astrocytes specifically in the denervated outer molecular layer of the dentate gyrus after entorhinal cortex lesion.","method":"In vitro stripe assay, entorhinal cortex lesion model, immunohistochemistry, Western blotting","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional stripe assay with defined outgrowth phenotype, in vivo lesion model, single lab","pmids":["15946856"],"is_preprint":false},{"year":2008,"finding":"Kilon (NEGR1) modulates synapse number in hippocampal neurons in a stage-dependent manner: overexpression decreased dendritic synapse number at early culture stages but increased synapse number at late culture stages, correlating with changes in subcellular localization (axonal/presynaptic early; dendritic postsynaptic late) and detergent solubility.","method":"Plasmid-mediated overexpression in cultured hippocampal neurons, synapse counting, immunocytochemistry, detergent extraction","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function with defined synaptic phenotype, multiple developmental stages examined, single lab","pmids":["18602091"],"is_preprint":false},{"year":2013,"finding":"NEGR1 controls the development of neurite arborization in vitro and in vivo; identified by cell surface biotinylation proteomics as a differentially expressed membrane protein during neuron maturation.","method":"Cell surface biotinylation assay, mass spectrometry, knockdown/overexpression in primary neurons, in vivo analysis","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell surface proteomics plus functional validation in vitro and in vivo, single lab","pmids":["24382801"],"is_preprint":false},{"year":2014,"finding":"NEGR1 is primarily localized to membrane lipid rafts at cell-to-cell contacting areas (GPI-anchored); overexpression of NEGR1 in ovarian cancer cells attenuates oncogenic phenotype, increases cell aggregation and neurite outgrowth, while NEGR1 depletion increases cell migration and invasion.","method":"Overexpression and siRNA knockdown, cell aggregation assay, migration/invasion assay, membrane fractionation","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined phenotypic readouts, single lab","pmids":["25057311"],"is_preprint":false},{"year":2016,"finding":"NEGR1 is shed from the neuronal membrane by the metalloprotease ADAM10 (ectodomain shedding); soluble/released NEGR1 promotes neurite outgrowth in a FGFR2- and P-ERK1/2-dependent manner. Pharmacological inhibition of ADAM10 impairs neurite tree maturation, which is rescued by treatment with soluble Negr1.","method":"Pharmacological ADAM10 inhibition, virus-mediated protein silencing in primary neurons, morphological analysis, rescue with soluble Negr1 treatment","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistatic rescue experiment, multiple genetic and pharmacological tools, defines ADAM10→Negr1→FGFR2→ERK pathway, replicated across conditions","pmids":["26793057"],"is_preprint":false},{"year":2016,"finding":"NEGR1 interacts with NPC2 (Niemann-Pick disease Type C2 protein) and increases its protein stability; NEGR1-deficient mouse embryonic fibroblast cells exhibit increased cholesterol levels and triglyceride contents, and ectopic NEGR1 expression relieves abnormal cholesterol accumulation in endosomal compartments.","method":"Co-immunoprecipitation, protein stability assay, cholesterol accumulation assay in NEGR1-deficient MEFs, ectopic expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding plus functional rescue in KO cells, single lab, two orthogonal methods","pmids":["27940359"],"is_preprint":false},{"year":2018,"finding":"NEGR1 physically interacts with FGFR2 and modulates FGFR2-dependent ERK and AKT signaling by decreasing FGFR2 degradation from the plasma membrane; downregulation of NEGR1 similarly affects neuronal migration and spine density during mouse cortical development as FGFR2 downregulation; FGFR2 overexpression rescues all defects caused by Negr1 knockdown in vivo.","method":"Co-immunoprecipitation, in utero electroporation knockdown/overexpression, spine density analysis, Western blotting for ERK/AKT signaling, Negr1 knockout mice","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistatic rescue in vivo, downstream signaling measured by multiple methods, replicated with both KD and KO models","pmids":["30059965"],"is_preprint":false},{"year":2019,"finding":"NEGR1 interacts with leukemia inhibitory factor receptor (LIFR) and modulates LIF-induced Lcn2 (lipocalin-2) expression in the hippocampus; Negr1-/- mice show decreased adult hippocampal neurogenesis, compromised LTP and mEPSC in the dentate gyrus; heterologous Lcn2 expression in hippocampal DG of negr1-/- mice rescued anxiety/depression-like behaviors and restored neurogenesis and mEPSC frequency.","method":"Co-immunoprecipitation (NEGR1-LIFR interaction), Negr1 knockout mice, LTP recording, mEPSC recording, AAV-mediated Lcn2 rescue, BrdU neurogenesis assay","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifies LIFR as binding partner, epistatic rescue with Lcn2 expression, multiple electrophysiological and behavioral readouts, single lab with multiple orthogonal methods","pmids":["30651602"],"is_preprint":false},{"year":2019,"finding":"Negr1 deficiency results in disrupted neurite sprouting during neuritogenesis, decreased number of parvalbumin-positive inhibitory interneurons in hippocampus, and neuroanatomical abnormalities including ventricle enlargement and reduced volumes of brain, corpus callosum, globus pallidus and hippocampus.","method":"Negr1-/- mouse model, in situ hybridization, brain morphological analysis (MRI), parvalbumin immunostaining, neuritogenesis assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with defined structural and cellular phenotypes, multiple orthogonal readouts, single lab","pmids":["30932003"],"is_preprint":false},{"year":2021,"finding":"NEGR1 associates with Na/K-ATPase beta1-subunit (ATP1B1), identified by yeast two-hybrid screening; the two proteins form a stable complex partially co-localizing in membrane lipid rafts; NEGR1 binds ATP1B1 at its C-terminus, away from the alpha subunit binding site.","method":"Yeast two-hybrid screening, co-immunoprecipitation, co-localization by immunofluorescence, domain mapping","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP confirmation plus co-localization, single lab","pmids":["32958118"],"is_preprint":false},{"year":2022,"finding":"IgLON4 (NEGR1 alias) is expressed in mouse skeletal muscle, localized to cell membrane at cell-to-cell adhesion sites, promotes myotube alignment and myogenic differentiation, and is linked to lipid raft accumulation during myogenic differentiation. IgLON4 inhibition disrupts myotube alignment.","method":"siRNA knockdown, immunofluorescence, CTX muscle injury model, directional myotube analysis, lipid raft staining","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined alignment phenotype, multiple methods, single lab","pmids":["36291131"],"is_preprint":false},{"year":2023,"finding":"Negr1 (as a GPI-anchored membrane protein and as a soluble form released by metalloprotease cleavage) induces ALK receptor downregulation in neuroblastoma; Negr1-derived peptides halt neuroblastoma progression in vitro and in vivo.","method":"Ectopic overexpression in neuroblastoma cells, in vitro growth assay, in vivo xenograft model, Negr1-derived peptide treatment, Western blotting for ALK","journal":"Pharmaceutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with in vitro and in vivo readouts, defined ALK downregulation mechanism, single lab","pmids":["37765276"],"is_preprint":false},{"year":2025,"finding":"NEGR1 promotes palmitoylation-dependent clearance of GAD65 (glutamic acid decarboxylase 65) from the plasma membrane and its targeting to plasma membrane-derived endocytic vesicles; NEGR1 deficiency results in non-synaptic accumulation of GAD65, increased plasma membrane-attached GAD65 at synaptic and extrasynaptic sites, reduced synaptic GABA levels, lower GABAergic synapse densities in the arcuate nucleus, and reduced body weight and blunted food reward responses.","method":"RNAseq in NEGR1-deficient mice, GAD65 plasma membrane biosensor, immunofluorescence, re-expression rescue, Negr1-/- mouse model, GABA level measurement","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel biosensor, transcriptomic identification, rescue by NEGR1 re-expression, multiple cellular and in vivo phenotypes, mechanistically defines palmitoylation-dependent GAD65 trafficking","pmids":["39676071"],"is_preprint":false},{"year":2025,"finding":"NEGR1 overexpression in the ventral hippocampus (vHIP) of mice leads to dendritic spine loss, synaptic ultrastructure abnormality, working memory impairment, and anxiety/depression-like behaviors; immunoprecipitation-mass spectrometry identified 67 high-confidence NEGR1-interacting proteins enriched in neurotransmitter exocytosis and synaptic vesicle endocytosis; transcriptomic profiling revealed enrichment in myelination-related pathways.","method":"Stereotaxic AAV injection for NEGR1 overexpression, behavioral assays, neuronal sparse labeling, transmission electron microscopy, immunoprecipitation-mass spectrometry, transcriptomic profiling, reporter gene assay, EMSA","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including EM ultrastructure, IP-MS interactome, transcriptomics, and behavioral readouts in a single rigorous study","pmids":["40382479"],"is_preprint":false},{"year":2025,"finding":"NEGR1 deficiency in mice reduces serum and testicular testosterone levels, downregulates key testosterone-synthesizing enzymes in Leydig cells, causes lipid droplet accumulation in testicular cells, disorganized testicular/epididymal structures, and increased abnormal sperm morphology; testosterone supplementation rescues impaired sexual behaviors and alleviates anxiety/depression-like phenotypes in Negr1-/- mice.","method":"Negr1-/- mouse model, hormone measurement, RT-PCR for steroidogenic enzyme expression, histological analysis, testosterone supplementation rescue","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with defined biochemical and histological phenotypes plus rescue experiment, single lab","pmids":["40886916"],"is_preprint":false},{"year":2024,"finding":"AP1AR-DT lncRNA reduces NEGR1 expression by competing for the transcriptional activator NRF1 at the overlapping binding site of the NEGR1 promoter region; overexpression of Negr1 in mPFC neurons of AP1AR-DT overexpressing mice ameliorates depressive and anxiety-like behaviors and normalizes reduced excitatory synaptic transmission.","method":"Chromatin immunoprecipitation, reporter gene assay, electrophysiological assays, behavioral tests, NEGR1 overexpression rescue in vivo","journal":"BMC medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP defines NRF1 competition mechanism, epistatic rescue in vivo, multiple orthogonal methods, single lab","pmids":["39558356"],"is_preprint":false},{"year":2014,"finding":"Decreased Negr1 expression in periventricular hypothalamic areas (via AAV-mediated knockdown) leads to increased body weight and food intake; both increased and decreased Negr1 levels lead to reduced locomotor activity and body temperature, indicating a role for hypothalamic Negr1 in energy balance regulation.","method":"AAV-mediated in vivo knockdown/overexpression in hypothalamus, body weight measurement, food intake monitoring, locomotor activity and body temperature measurement","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional in vivo manipulation with defined physiological readouts, single lab","pmids":["25077509"],"is_preprint":false},{"year":2024,"finding":"NEGR1 deficiency in mice increases inhibitory inputs to mitral cells in the olfactory bulb, decreases mitral cell excitability, and reduces adult neurogenesis in the subventricular zone (diminished integration of newly generated inhibitory neurons into the olfactory bulb), resulting in aberrant olfactory habituation/dishabituation and impaired affective discrimination.","method":"Whole-cell patch clamp electrophysiology, BrdU neurogenesis assay, olfactory behavioral testing, Negr1-/- mouse model","journal":"Biological psychiatry global open science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology plus neurogenesis assay with defined behavioral phenotype, single lab","pmids":["39170714"],"is_preprint":false}],"current_model":"NEGR1 is a GPI-anchored IgLON-family cell adhesion molecule localized to lipid rafts and synaptic membranes that regulates neurite arborization, synapse number, and dendritic spine density by physically interacting with FGFR2 (reducing its degradation and sustaining ERK/AKT signaling), LIFR (modulating LIF-dependent Lcn2 expression for adult neurogenesis), ADAM10 (which sheds soluble NEGR1 to act as a paracrine FGFR2 activator), ATP1B1, and NPC2; within neurons, NEGR1 promotes palmitoylation-dependent GAD65 trafficking to synaptic vesicles to maintain inhibitory GABA synthesis, and loss of NEGR1 disrupts GABAergic interneuron density, olfactory neurogenesis, monoaminergic signaling, testosterone production in Leydig cells, and hypothalamic energy balance, while NEGR1 overexpression in the ventral hippocampus causes spine loss and anxiety/depression-like behaviors through interactors enriched in synaptic vesicle exocytosis and myelination pathways."},"narrative":{"mechanistic_narrative":"NEGR1 (Kilon) is a brain-enriched, GPI-anchored cell adhesion molecule of the IgLON immunoglobulin superfamily that resides in Triton-insoluble lipid raft membranes and at cell-to-cell contact sites, where it governs neurite arborization, synapse number, and dendritic spine density during neural development [PMID:10075727, PMID:24382801, PMID:30059965]. It engages in both homophilic and heterophilic adhesion (e.g. with OBCAM) and is concentrated at postsynaptic membranes [PMID:12617969]. NEGR1 acts largely as a growth-factor signaling modulator: it physically interacts with FGFR2, reduces FGFR2 degradation from the plasma membrane, and sustains downstream ERK and AKT signaling, with FGFR2 overexpression rescuing the neuronal migration and spine defects of Negr1 loss [PMID:30059965]. The metalloprotease ADAM10 sheds the NEGR1 ectodomain, and this soluble form promotes neurite outgrowth in an FGFR2- and ERK1/2-dependent manner [PMID:26793057]. NEGR1 additionally binds LIFR to control LIF-induced Lcn2 expression supporting adult hippocampal neurogenesis, synaptic plasticity, and affective behavior [PMID:30651602], and binds NPC2 and the Na/K-ATPase beta1-subunit ATP1B1, linking it to cholesterol handling and membrane raft organization [PMID:27940359, PMID:32958118]. Within neurons NEGR1 promotes palmitoylation-dependent clearance and vesicular targeting of GAD65 to maintain inhibitory GABA synthesis, and its loss reduces parvalbumin interneuron numbers and GABAergic synapse density [PMID:30932003, PMID:39676071]. Loss of NEGR1 disrupts hypothalamic energy balance, olfactory neurogenesis, and Leydig-cell testosterone production, while its dysregulation in limbic circuits produces anxiety- and depression-like behaviors [PMID:39676071, PMID:40382479, PMID:40886916, PMID:25077509, PMID:39170714]. Beyond the nervous system NEGR1 (IgLON4) modulates myogenic differentiation and constrains tumor cell migration and growth in ovarian cancer and neuroblastoma [PMID:25057311, PMID:36291131, PMID:37765276].","teleology":[{"year":1999,"claim":"Established the molecular identity of NEGR1 as a GPI-anchored IgLON family adhesion protein, defining its membrane attachment and raft residence as the structural basis for all later signaling roles.","evidence":"cDNA cloning, PI-PLC solubilization, deglycosylation, and lipid raft fractionation in rat brain","pmids":["10075727"],"confidence":"High","gaps":["No binding partner or signaling output identified","Function inferred only from family membership and localization"]},{"year":2003,"claim":"Showed NEGR1 mediates both homophilic and heterophilic adhesion and is postsynaptically enriched, framing it as an adhesion molecule acting at synaptic contacts.","evidence":"Cross-linker, immunoprecipitation, and EM immunohistochemistry in rat cortex/hippocampus","pmids":["12617969"],"confidence":"High","gaps":["Functional consequence of OBCAM binding not tested","No downstream signaling defined"]},{"year":2005,"claim":"Demonstrated NEGR1 actively promotes neurite outgrowth and axon attraction, moving it from a static adhesion marker to a regulator of process growth.","evidence":"In vitro stripe assay and entorhinal cortex lesion model with immunohistochemistry","pmids":["15946856"],"confidence":"Medium","gaps":["Receptor/signaling mediating outgrowth unknown","Single lab"]},{"year":2008,"claim":"Revealed that NEGR1 controls synapse number in a developmental-stage-dependent manner correlated with subcellular relocalization, indicating context-dependent function.","evidence":"Overexpression in cultured hippocampal neurons with synapse counting and detergent extraction","pmids":["18602091"],"confidence":"Medium","gaps":["Mechanism linking localization shift to synapse change unresolved","Gain-of-function only"]},{"year":2016,"claim":"Defined the ADAM10→soluble NEGR1→FGFR2→ERK axis, showing the shed ectodomain acts as a diffusible neurite-promoting ligand.","evidence":"ADAM10 pharmacological inhibition and silencing in primary neurons with rescue by soluble Negr1","pmids":["26793057"],"confidence":"High","gaps":["Direct soluble NEGR1–FGFR2 binding not biochemically isolated","Physiological extent of shedding in vivo unquantified"]},{"year":2016,"claim":"Linked NEGR1 to lipid metabolism by showing it stabilizes NPC2 and limits cholesterol/triglyceride accumulation, extending its role beyond adhesion.","evidence":"Co-IP, protein stability assay, and cholesterol rescue in NEGR1-deficient MEFs","pmids":["27940359"],"confidence":"Medium","gaps":["Whether NPC2 stabilization underlies neural phenotypes untested","Single lab, two methods"]},{"year":2018,"claim":"Identified FGFR2 as a direct NEGR1 partner whose plasma-membrane stability NEGR1 sustains, providing the core mechanism for NEGR1 control of cortical neuron migration and spine density.","evidence":"Reciprocal Co-IP, in utero electroporation, ERK/AKT immunoblotting, KO mice, and FGFR2 rescue","pmids":["30059965"],"confidence":"High","gaps":["Molecular basis of NEGR1-dependent FGFR2 stabilization unresolved","Stoichiometry of NEGR1–FGFR2 complex unknown"]},{"year":2019,"claim":"Established a NEGR1–LIFR–Lcn2 axis regulating adult hippocampal neurogenesis, plasticity, and affective behavior, with Lcn2 sufficient to rescue knockout phenotypes.","evidence":"Co-IP, Negr1 KO mice, LTP/mEPSC recording, AAV-Lcn2 rescue, and BrdU neurogenesis","pmids":["30651602"],"confidence":"High","gaps":["How NEGR1 modulates LIFR signaling mechanistically not defined","Relationship to FGFR2 pathway unaddressed"]},{"year":2019,"claim":"Tied NEGR1 loss to reduced parvalbumin interneurons and gross neuroanatomical defects, anchoring its behavioral roles in inhibitory circuit and structural development.","evidence":"Negr1 KO MRI morphometry, in situ hybridization, parvalbumin immunostaining","pmids":["30932003"],"confidence":"Medium","gaps":["Cellular mechanism of interneuron loss unresolved","Correlative structural readouts"]},{"year":2021,"claim":"Identified ATP1B1 as a raft-localized NEGR1 partner via its C-terminus, connecting NEGR1 to Na/K-ATPase complexes in membrane microdomains.","evidence":"Yeast two-hybrid, Co-IP, co-localization, and domain mapping","pmids":["32958118"],"confidence":"Medium","gaps":["Functional consequence of ATP1B1 binding untested","No in vivo validation"]},{"year":2025,"claim":"Defined a mechanistic role for NEGR1 in palmitoylation-dependent GAD65 trafficking that maintains inhibitory GABA synthesis and hypothalamic GABAergic synapse density.","evidence":"RNAseq, GAD65 plasma membrane biosensor, re-expression rescue, and GABA measurement in Negr1 KO mice","pmids":["39676071"],"confidence":"High","gaps":["Whether NEGR1 directly regulates the palmitoylation machinery unknown","Link to FGFR2/LIFR pathways not established"]},{"year":2025,"claim":"Showed NEGR1 overexpression in ventral hippocampus drives spine loss and affective deficits and catalogued its synaptic interactome, indicating dose-dependent disruption of synaptic vesicle and myelination programs.","evidence":"AAV overexpression, EM, IP-MS interactome, transcriptomics, and behavioral assays","pmids":["40382479"],"confidence":"High","gaps":["Which interactors mediate the spine-loss phenotype undefined","Direct vs indirect transcriptomic effects unresolved"]},{"year":2025,"claim":"Extended NEGR1 function to peripheral steroidogenesis, showing its loss impairs Leydig-cell testosterone synthesis with testosterone supplementation rescuing behavioral phenotypes.","evidence":"Negr1 KO hormone measurement, steroidogenic enzyme RT-PCR, histology, and testosterone rescue","pmids":["40886916"],"confidence":"Medium","gaps":["Molecular mechanism in Leydig cells unknown","Link to lipid/cholesterol handling not directly tested"]},{"year":null,"claim":"How NEGR1 integrates its multiple receptor partnerships (FGFR2, LIFR, ATP1B1, NPC2) into a unified raft-organizing or signaling function, and how the same molecule produces opposing phenotypes upon loss versus overexpression, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of NEGR1 in complex with any receptor","Mechanism reconciling dose-dependent bidirectional synaptic effects unknown","Hierarchy among adhesion, FGFR2 stabilization, and lipid functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8,9]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,8,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[14,15,19]}],"complexes":[],"partners":["FGFR2","LIFR","ADAM10","NPC2","ATP1B1","OBCAM","GAD65"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z3B1","full_name":"Neuronal growth regulator 1","aliases":["IgLON family member 4"],"length_aa":354,"mass_kda":38.7,"function":"May be involved in cell-adhesion. May function as a trans-neural growth-promoting factor in regenerative axon sprouting in the mammalian brain (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q7Z3B1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NEGR1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NEGR1","total_profiled":1310},"omim":[{"mim_id":"613173","title":"NEURONAL GROWTH REGULATOR 1; NEGR1","url":"https://www.omim.org/entry/613173"},{"mim_id":"601665","title":"OBESITY","url":"https://www.omim.org/entry/601665"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Actin filaments","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":31.2}],"url":"https://www.proteinatlas.org/search/NEGR1"},"hgnc":{"alias_symbol":["KILON","MGC46680","Ntra","IGLON4"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z3B1","domains":[{"cath_id":"2.60.40.10","chopping":"43-136","consensus_level":"high","plddt":92.9584,"start":43,"end":136},{"cath_id":"2.60.40.10","chopping":"138-222","consensus_level":"medium","plddt":95.6989,"start":138,"end":222},{"cath_id":"2.60.40.10","chopping":"224-311","consensus_level":"medium","plddt":94.4919,"start":224,"end":311}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z3B1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z3B1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z3B1-F1-predicted_aligned_error_v6.png","plddt_mean":81.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NEGR1","jax_strain_url":"https://www.jax.org/strain/search?query=NEGR1"},"sequence":{"accession":"Q7Z3B1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z3B1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z3B1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z3B1"}},"corpus_meta":[{"pmid":"2999766","id":"PMC_2999766","title":"Products of nitrogen regulatory genes ntrA and ntrC of enteric bacteria activate glnA transcription in vitro: evidence that the ntrA product is a sigma factor.","date":"1985","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2999766","citation_count":327,"is_preprint":false},{"pmid":"3034856","id":"PMC_3034856","title":"Rhizobium meliloti ntrA (rpoN) gene is required for diverse metabolic functions.","date":"1987","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/3034856","citation_count":198,"is_preprint":false},{"pmid":"10075727","id":"PMC_10075727","title":"Characterization of a novel rat brain glycosylphosphatidylinositol-anchored protein (Kilon), a member of the IgLON cell adhesion molecule family.","date":"1999","source":"The Journal of biological 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phosphatidylinositol-specific phospholipase C solubilization, Western blotting, peptide N-glycosidase F deglycosylation, immunostaining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical characterization with multiple orthogonal methods (cloning, lipid raft fractionation, immunostaining), foundational characterization paper\",\n      \"pmids\": [\"10075727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kilon (NEGR1) and OBCAM interact both heterophilically and homophilically, as demonstrated by cross-linker and immunoprecipitation binding analysis; Kilon is localized mainly at postsynaptic sites of dendritic and somatic synapses in adult cerebral cortex and hippocampus, and is present predominantly in the Triton-insoluble fraction.\",\n      \"method\": \"Cross-linker treatment, immunoprecipitation, electron microscopic immunohistochemistry, Western blotting, subcellular fractionation\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated by cross-linker/IP, ultrastructural localization by EM, multiple orthogonal methods in single study\",\n      \"pmids\": [\"12617969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Neurotractin/kilon (NEGR1) promotes neurite outgrowth: in vitro stripe assays showed that neurotractin/kilon attracts hippocampal axons and astroglial neurotractin/kilon promotes neurite outgrowth; expression is upregulated on reactive astrocytes specifically in the denervated outer molecular layer of the dentate gyrus after entorhinal cortex lesion.\",\n      \"method\": \"In vitro stripe assay, entorhinal cortex lesion model, immunohistochemistry, Western blotting\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional stripe assay with defined outgrowth phenotype, in vivo lesion model, single lab\",\n      \"pmids\": [\"15946856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kilon (NEGR1) modulates synapse number in hippocampal neurons in a stage-dependent manner: overexpression decreased dendritic synapse number at early culture stages but increased synapse number at late culture stages, correlating with changes in subcellular localization (axonal/presynaptic early; dendritic postsynaptic late) and detergent solubility.\",\n      \"method\": \"Plasmid-mediated overexpression in cultured hippocampal neurons, synapse counting, immunocytochemistry, detergent extraction\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function with defined synaptic phenotype, multiple developmental stages examined, single lab\",\n      \"pmids\": [\"18602091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NEGR1 controls the development of neurite arborization in vitro and in vivo; identified by cell surface biotinylation proteomics as a differentially expressed membrane protein during neuron maturation.\",\n      \"method\": \"Cell surface biotinylation assay, mass spectrometry, knockdown/overexpression in primary neurons, in vivo analysis\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell surface proteomics plus functional validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"24382801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NEGR1 is primarily localized to membrane lipid rafts at cell-to-cell contacting areas (GPI-anchored); overexpression of NEGR1 in ovarian cancer cells attenuates oncogenic phenotype, increases cell aggregation and neurite outgrowth, while NEGR1 depletion increases cell migration and invasion.\",\n      \"method\": \"Overexpression and siRNA knockdown, cell aggregation assay, migration/invasion assay, membrane fractionation\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"25057311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NEGR1 is shed from the neuronal membrane by the metalloprotease ADAM10 (ectodomain shedding); soluble/released NEGR1 promotes neurite outgrowth in a FGFR2- and P-ERK1/2-dependent manner. Pharmacological inhibition of ADAM10 impairs neurite tree maturation, which is rescued by treatment with soluble Negr1.\",\n      \"method\": \"Pharmacological ADAM10 inhibition, virus-mediated protein silencing in primary neurons, morphological analysis, rescue with soluble Negr1 treatment\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistatic rescue experiment, multiple genetic and pharmacological tools, defines ADAM10→Negr1→FGFR2→ERK pathway, replicated across conditions\",\n      \"pmids\": [\"26793057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NEGR1 interacts with NPC2 (Niemann-Pick disease Type C2 protein) and increases its protein stability; NEGR1-deficient mouse embryonic fibroblast cells exhibit increased cholesterol levels and triglyceride contents, and ectopic NEGR1 expression relieves abnormal cholesterol accumulation in endosomal compartments.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, cholesterol accumulation assay in NEGR1-deficient MEFs, ectopic expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding plus functional rescue in KO cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"27940359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NEGR1 physically interacts with FGFR2 and modulates FGFR2-dependent ERK and AKT signaling by decreasing FGFR2 degradation from the plasma membrane; downregulation of NEGR1 similarly affects neuronal migration and spine density during mouse cortical development as FGFR2 downregulation; FGFR2 overexpression rescues all defects caused by Negr1 knockdown in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in utero electroporation knockdown/overexpression, spine density analysis, Western blotting for ERK/AKT signaling, Negr1 knockout mice\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistatic rescue in vivo, downstream signaling measured by multiple methods, replicated with both KD and KO models\",\n      \"pmids\": [\"30059965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NEGR1 interacts with leukemia inhibitory factor receptor (LIFR) and modulates LIF-induced Lcn2 (lipocalin-2) expression in the hippocampus; Negr1-/- mice show decreased adult hippocampal neurogenesis, compromised LTP and mEPSC in the dentate gyrus; heterologous Lcn2 expression in hippocampal DG of negr1-/- mice rescued anxiety/depression-like behaviors and restored neurogenesis and mEPSC frequency.\",\n      \"method\": \"Co-immunoprecipitation (NEGR1-LIFR interaction), Negr1 knockout mice, LTP recording, mEPSC recording, AAV-mediated Lcn2 rescue, BrdU neurogenesis assay\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifies LIFR as binding partner, epistatic rescue with Lcn2 expression, multiple electrophysiological and behavioral readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30651602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Negr1 deficiency results in disrupted neurite sprouting during neuritogenesis, decreased number of parvalbumin-positive inhibitory interneurons in hippocampus, and neuroanatomical abnormalities including ventricle enlargement and reduced volumes of brain, corpus callosum, globus pallidus and hippocampus.\",\n      \"method\": \"Negr1-/- mouse model, in situ hybridization, brain morphological analysis (MRI), parvalbumin immunostaining, neuritogenesis assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with defined structural and cellular phenotypes, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"30932003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEGR1 associates with Na/K-ATPase beta1-subunit (ATP1B1), identified by yeast two-hybrid screening; the two proteins form a stable complex partially co-localizing in membrane lipid rafts; NEGR1 binds ATP1B1 at its C-terminus, away from the alpha subunit binding site.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, co-localization by immunofluorescence, domain mapping\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP confirmation plus co-localization, single lab\",\n      \"pmids\": [\"32958118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IgLON4 (NEGR1 alias) is expressed in mouse skeletal muscle, localized to cell membrane at cell-to-cell adhesion sites, promotes myotube alignment and myogenic differentiation, and is linked to lipid raft accumulation during myogenic differentiation. IgLON4 inhibition disrupts myotube alignment.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, CTX muscle injury model, directional myotube analysis, lipid raft staining\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined alignment phenotype, multiple methods, single lab\",\n      \"pmids\": [\"36291131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Negr1 (as a GPI-anchored membrane protein and as a soluble form released by metalloprotease cleavage) induces ALK receptor downregulation in neuroblastoma; Negr1-derived peptides halt neuroblastoma progression in vitro and in vivo.\",\n      \"method\": \"Ectopic overexpression in neuroblastoma cells, in vitro growth assay, in vivo xenograft model, Negr1-derived peptide treatment, Western blotting for ALK\",\n      \"journal\": \"Pharmaceutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with in vitro and in vivo readouts, defined ALK downregulation mechanism, single lab\",\n      \"pmids\": [\"37765276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NEGR1 promotes palmitoylation-dependent clearance of GAD65 (glutamic acid decarboxylase 65) from the plasma membrane and its targeting to plasma membrane-derived endocytic vesicles; NEGR1 deficiency results in non-synaptic accumulation of GAD65, increased plasma membrane-attached GAD65 at synaptic and extrasynaptic sites, reduced synaptic GABA levels, lower GABAergic synapse densities in the arcuate nucleus, and reduced body weight and blunted food reward responses.\",\n      \"method\": \"RNAseq in NEGR1-deficient mice, GAD65 plasma membrane biosensor, immunofluorescence, re-expression rescue, Negr1-/- mouse model, GABA level measurement\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel biosensor, transcriptomic identification, rescue by NEGR1 re-expression, multiple cellular and in vivo phenotypes, mechanistically defines palmitoylation-dependent GAD65 trafficking\",\n      \"pmids\": [\"39676071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NEGR1 overexpression in the ventral hippocampus (vHIP) of mice leads to dendritic spine loss, synaptic ultrastructure abnormality, working memory impairment, and anxiety/depression-like behaviors; immunoprecipitation-mass spectrometry identified 67 high-confidence NEGR1-interacting proteins enriched in neurotransmitter exocytosis and synaptic vesicle endocytosis; transcriptomic profiling revealed enrichment in myelination-related pathways.\",\n      \"method\": \"Stereotaxic AAV injection for NEGR1 overexpression, behavioral assays, neuronal sparse labeling, transmission electron microscopy, immunoprecipitation-mass spectrometry, transcriptomic profiling, reporter gene assay, EMSA\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including EM ultrastructure, IP-MS interactome, transcriptomics, and behavioral readouts in a single rigorous study\",\n      \"pmids\": [\"40382479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NEGR1 deficiency in mice reduces serum and testicular testosterone levels, downregulates key testosterone-synthesizing enzymes in Leydig cells, causes lipid droplet accumulation in testicular cells, disorganized testicular/epididymal structures, and increased abnormal sperm morphology; testosterone supplementation rescues impaired sexual behaviors and alleviates anxiety/depression-like phenotypes in Negr1-/- mice.\",\n      \"method\": \"Negr1-/- mouse model, hormone measurement, RT-PCR for steroidogenic enzyme expression, histological analysis, testosterone supplementation rescue\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with defined biochemical and histological phenotypes plus rescue experiment, single lab\",\n      \"pmids\": [\"40886916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AP1AR-DT lncRNA reduces NEGR1 expression by competing for the transcriptional activator NRF1 at the overlapping binding site of the NEGR1 promoter region; overexpression of Negr1 in mPFC neurons of AP1AR-DT overexpressing mice ameliorates depressive and anxiety-like behaviors and normalizes reduced excitatory synaptic transmission.\",\n      \"method\": \"Chromatin immunoprecipitation, reporter gene assay, electrophysiological assays, behavioral tests, NEGR1 overexpression rescue in vivo\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP defines NRF1 competition mechanism, epistatic rescue in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39558356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Decreased Negr1 expression in periventricular hypothalamic areas (via AAV-mediated knockdown) leads to increased body weight and food intake; both increased and decreased Negr1 levels lead to reduced locomotor activity and body temperature, indicating a role for hypothalamic Negr1 in energy balance regulation.\",\n      \"method\": \"AAV-mediated in vivo knockdown/overexpression in hypothalamus, body weight measurement, food intake monitoring, locomotor activity and body temperature measurement\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional in vivo manipulation with defined physiological readouts, single lab\",\n      \"pmids\": [\"25077509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NEGR1 deficiency in mice increases inhibitory inputs to mitral cells in the olfactory bulb, decreases mitral cell excitability, and reduces adult neurogenesis in the subventricular zone (diminished integration of newly generated inhibitory neurons into the olfactory bulb), resulting in aberrant olfactory habituation/dishabituation and impaired affective discrimination.\",\n      \"method\": \"Whole-cell patch clamp electrophysiology, BrdU neurogenesis assay, olfactory behavioral testing, Negr1-/- mouse model\",\n      \"journal\": \"Biological psychiatry global open science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology plus neurogenesis assay with defined behavioral phenotype, single lab\",\n      \"pmids\": [\"39170714\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NEGR1 is a GPI-anchored IgLON-family cell adhesion molecule localized to lipid rafts and synaptic membranes that regulates neurite arborization, synapse number, and dendritic spine density by physically interacting with FGFR2 (reducing its degradation and sustaining ERK/AKT signaling), LIFR (modulating LIF-dependent Lcn2 expression for adult neurogenesis), ADAM10 (which sheds soluble NEGR1 to act as a paracrine FGFR2 activator), ATP1B1, and NPC2; within neurons, NEGR1 promotes palmitoylation-dependent GAD65 trafficking to synaptic vesicles to maintain inhibitory GABA synthesis, and loss of NEGR1 disrupts GABAergic interneuron density, olfactory neurogenesis, monoaminergic signaling, testosterone production in Leydig cells, and hypothalamic energy balance, while NEGR1 overexpression in the ventral hippocampus causes spine loss and anxiety/depression-like behaviors through interactors enriched in synaptic vesicle exocytosis and myelination pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NEGR1 (Kilon) is a brain-enriched, GPI-anchored cell adhesion molecule of the IgLON immunoglobulin superfamily that resides in Triton-insoluble lipid raft membranes and at cell-to-cell contact sites, where it governs neurite arborization, synapse number, and dendritic spine density during neural development [#0, #4, #8]. It engages in both homophilic and heterophilic adhesion (e.g. with OBCAM) and is concentrated at postsynaptic membranes [#1]. NEGR1 acts largely as a growth-factor signaling modulator: it physically interacts with FGFR2, reduces FGFR2 degradation from the plasma membrane, and sustains downstream ERK and AKT signaling, with FGFR2 overexpression rescuing the neuronal migration and spine defects of Negr1 loss [#8]. The metalloprotease ADAM10 sheds the NEGR1 ectodomain, and this soluble form promotes neurite outgrowth in an FGFR2- and ERK1/2-dependent manner [#6]. NEGR1 additionally binds LIFR to control LIF-induced Lcn2 expression supporting adult hippocampal neurogenesis, synaptic plasticity, and affective behavior [#9], and binds NPC2 and the Na/K-ATPase beta1-subunit ATP1B1, linking it to cholesterol handling and membrane raft organization [#7, #11]. Within neurons NEGR1 promotes palmitoylation-dependent clearance and vesicular targeting of GAD65 to maintain inhibitory GABA synthesis, and its loss reduces parvalbumin interneuron numbers and GABAergic synapse density [#10, #14]. Loss of NEGR1 disrupts hypothalamic energy balance, olfactory neurogenesis, and Leydig-cell testosterone production, while its dysregulation in limbic circuits produces anxiety- and depression-like behaviors [#14, #15, #16, #18, #19]. Beyond the nervous system NEGR1 (IgLON4) modulates myogenic differentiation and constrains tumor cell migration and growth in ovarian cancer and neuroblastoma [#5, #12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the molecular identity of NEGR1 as a GPI-anchored IgLON family adhesion protein, defining its membrane attachment and raft residence as the structural basis for all later signaling roles.\",\n      \"evidence\": \"cDNA cloning, PI-PLC solubilization, deglycosylation, and lipid raft fractionation in rat brain\",\n      \"pmids\": [\"10075727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partner or signaling output identified\", \"Function inferred only from family membership and localization\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed NEGR1 mediates both homophilic and heterophilic adhesion and is postsynaptically enriched, framing it as an adhesion molecule acting at synaptic contacts.\",\n      \"evidence\": \"Cross-linker, immunoprecipitation, and EM immunohistochemistry in rat cortex/hippocampus\",\n      \"pmids\": [\"12617969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of OBCAM binding not tested\", \"No downstream signaling defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated NEGR1 actively promotes neurite outgrowth and axon attraction, moving it from a static adhesion marker to a regulator of process growth.\",\n      \"evidence\": \"In vitro stripe assay and entorhinal cortex lesion model with immunohistochemistry\",\n      \"pmids\": [\"15946856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/signaling mediating outgrowth unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed that NEGR1 controls synapse number in a developmental-stage-dependent manner correlated with subcellular relocalization, indicating context-dependent function.\",\n      \"evidence\": \"Overexpression in cultured hippocampal neurons with synapse counting and detergent extraction\",\n      \"pmids\": [\"18602091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking localization shift to synapse change unresolved\", \"Gain-of-function only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the ADAM10\\u2192soluble NEGR1\\u2192FGFR2\\u2192ERK axis, showing the shed ectodomain acts as a diffusible neurite-promoting ligand.\",\n      \"evidence\": \"ADAM10 pharmacological inhibition and silencing in primary neurons with rescue by soluble Negr1\",\n      \"pmids\": [\"26793057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct soluble NEGR1\\u2013FGFR2 binding not biochemically isolated\", \"Physiological extent of shedding in vivo unquantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked NEGR1 to lipid metabolism by showing it stabilizes NPC2 and limits cholesterol/triglyceride accumulation, extending its role beyond adhesion.\",\n      \"evidence\": \"Co-IP, protein stability assay, and cholesterol rescue in NEGR1-deficient MEFs\",\n      \"pmids\": [\"27940359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NPC2 stabilization underlies neural phenotypes untested\", \"Single lab, two methods\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FGFR2 as a direct NEGR1 partner whose plasma-membrane stability NEGR1 sustains, providing the core mechanism for NEGR1 control of cortical neuron migration and spine density.\",\n      \"evidence\": \"Reciprocal Co-IP, in utero electroporation, ERK/AKT immunoblotting, KO mice, and FGFR2 rescue\",\n      \"pmids\": [\"30059965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of NEGR1-dependent FGFR2 stabilization unresolved\", \"Stoichiometry of NEGR1\\u2013FGFR2 complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a NEGR1\\u2013LIFR\\u2013Lcn2 axis regulating adult hippocampal neurogenesis, plasticity, and affective behavior, with Lcn2 sufficient to rescue knockout phenotypes.\",\n      \"evidence\": \"Co-IP, Negr1 KO mice, LTP/mEPSC recording, AAV-Lcn2 rescue, and BrdU neurogenesis\",\n      \"pmids\": [\"30651602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NEGR1 modulates LIFR signaling mechanistically not defined\", \"Relationship to FGFR2 pathway unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tied NEGR1 loss to reduced parvalbumin interneurons and gross neuroanatomical defects, anchoring its behavioral roles in inhibitory circuit and structural development.\",\n      \"evidence\": \"Negr1 KO MRI morphometry, in situ hybridization, parvalbumin immunostaining\",\n      \"pmids\": [\"30932003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mechanism of interneuron loss unresolved\", \"Correlative structural readouts\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ATP1B1 as a raft-localized NEGR1 partner via its C-terminus, connecting NEGR1 to Na/K-ATPase complexes in membrane microdomains.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, co-localization, and domain mapping\",\n      \"pmids\": [\"32958118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ATP1B1 binding untested\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a mechanistic role for NEGR1 in palmitoylation-dependent GAD65 trafficking that maintains inhibitory GABA synthesis and hypothalamic GABAergic synapse density.\",\n      \"evidence\": \"RNAseq, GAD65 plasma membrane biosensor, re-expression rescue, and GABA measurement in Negr1 KO mice\",\n      \"pmids\": [\"39676071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NEGR1 directly regulates the palmitoylation machinery unknown\", \"Link to FGFR2/LIFR pathways not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed NEGR1 overexpression in ventral hippocampus drives spine loss and affective deficits and catalogued its synaptic interactome, indicating dose-dependent disruption of synaptic vesicle and myelination programs.\",\n      \"evidence\": \"AAV overexpression, EM, IP-MS interactome, transcriptomics, and behavioral assays\",\n      \"pmids\": [\"40382479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which interactors mediate the spine-loss phenotype undefined\", \"Direct vs indirect transcriptomic effects unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended NEGR1 function to peripheral steroidogenesis, showing its loss impairs Leydig-cell testosterone synthesis with testosterone supplementation rescuing behavioral phenotypes.\",\n      \"evidence\": \"Negr1 KO hormone measurement, steroidogenic enzyme RT-PCR, histology, and testosterone rescue\",\n      \"pmids\": [\"40886916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism in Leydig cells unknown\", \"Link to lipid/cholesterol handling not directly tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NEGR1 integrates its multiple receptor partnerships (FGFR2, LIFR, ATP1B1, NPC2) into a unified raft-organizing or signaling function, and how the same molecule produces opposing phenotypes upon loss versus overexpression, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of NEGR1 in complex with any receptor\", \"Mechanism reconciling dose-dependent bidirectional synaptic effects unknown\", \"Hierarchy among adhesion, FGFR2 stabilization, and lipid functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8, 9]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 8, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [14, 15, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FGFR2\", \"LIFR\", \"ADAM10\", \"NPC2\", \"ATP1B1\", \"OBCAM\", \"GAD65\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}