{"gene":"CADM3","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2005,"finding":"Necl-1/CADM3 exhibits Ca2+-independent homophilic cell-cell adhesion activity, and Ca2+-independent heterophilic adhesion with Necl-2/SynCAM1, nectin-1, and nectin-3, but not with Necl-5 or nectin-2. Its C-terminal cytoplasmic region binds membrane-associated guanylate kinase (MAGUK) subfamily members containing the L27 domain (Dlg3, Pals2, and CASK), but does not bind afadin.","method":"Cell-cell adhesion assays, co-immunoprecipitation, domain mapping","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal binding assays (adhesion assay, Co-IP, domain mapping) in a single focused study; findings replicated conceptually by subsequent structural and functional studies","pmids":["15741237"],"is_preprint":false},{"year":2005,"finding":"Necl-1/CADM3 localizes at non-junctional contact sites of presynaptic nerve terminals, axons, and glial cell processes (axon bundles and myelinated axons) as determined by immunofluorescence and immunoelectron microscopy, consistent with roles in synapse formation, axon bundling, and myelination.","method":"Immunofluorescence microscopy, immunoelectron microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct immunoelectron microscopy localization with high spatial resolution, replicated by multiple subsequent studies","pmids":["15741237"],"is_preprint":false},{"year":2006,"finding":"The N-terminal Ig-like V domain of Necl-1/CADM3 is sufficient for homophilic interaction; the protein crystallizes as a dimer confirmed by size-exclusion chromatography and chemical cross-linking. Mutagenesis identified Phe82 as a key residue for adhesion activity.","method":"X-ray crystallography (2.4 Å resolution), size-exclusion chromatography, chemical cross-linking, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with mutagenesis and biochemical validation in one rigorous study","pmids":["16467305"],"is_preprint":false},{"year":2009,"finding":"Loss of NECL1/CADM3 expression in glioma is caused at least partly by histone deacetylation (not CpG methylation). HDAC inhibitor TSA reactivates NECL1 expression. Sp1 binds HDAC1 at the NECL1 promoter in untreated glioma cells, and switches to binding p300/CBP after TSA treatment. Re-expression of NECL1 in glioma cells induces cell cycle arrest and suppresses proliferation in vitro and tumor growth in vivo.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), DNA bisulfite sequencing, HDAC activity assay, xenograft model","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, reporter assay, in vivo model) in a single study establishing the epigenetic regulatory mechanism","pmids":["19062177"],"is_preprint":false},{"year":2009,"finding":"NECL1/CADM3 expression in glioma cells inhibits migration and invasion (scratch and Transwell assays), reduces extracellular metalloproteinase activities, and promotes potential differentiation toward an astrocyte phenotype with upregulation of GFAP.","method":"Scratch assay, Transwell assay, metalloproteinase activity measurement, Western blot for GFAP","journal":"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, standard cellular assays with functional readouts but limited mechanistic depth","pmids":["20078932"],"is_preprint":false},{"year":2008,"finding":"Re-expression of NECL1/CADM3 in the NECL1-silent T98G glioma cell line decreases cell growth rate and increases apoptosis, establishing a role in restraining glioma cell proliferation.","method":"Cell growth curve, flow cytometry, Hoechst staining","journal":"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, loss/gain-of-function with defined cellular phenotype but limited mechanistic pathway placement","pmids":["18686605"],"is_preprint":false},{"year":2008,"finding":"Overexpression of Necl1/CADM3 in HEK293 cells induces synapse formation when co-cultured with neurons. Ectopic expression of Necl1 in primary neurons increases synapse density. Necl1 partially localizes to synaptosomes.","method":"Co-culture synapse formation assay, immunofluorescence, Western blot, synaptosome fractionation","journal":"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, gain-of-function with functional synaptic readout but limited orthogonal validation","pmids":["18686604"],"is_preprint":false},{"year":2011,"finding":"Zebrafish cadm3 and cadm2a bind heterophilically: in vitro binding assays show cadm3 preferentially binds cadm4, while cadm2a preferentially binds cadm1, mirroring tetrapod binding preferences.","method":"In vitro binding assay with subtype-specific antibodies","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding assay in vitro, single lab, single method","pmids":["21456004"],"is_preprint":false},{"year":2016,"finding":"shRNA-mediated knockdown of axonal Cadm3 promotes Schwann cell myelination in DRG neuron/Schwann cell co-cultures, while overexpression of Cadm3 nearly abolishes myelin segment formation. SCG neurons (which do not support myelination) express higher Cadm3 than DRG neurons; Cadm3 knockdown in SCG neurons enables myelination. The extracellular domain of Cadm3 interferes dose-dependently with activation of ErbB3 and the PI3K/Akt pro-myelinating pathway but does not affect the Mek/Erk1/2 pathway.","method":"shRNA knockdown, overexpression in vitro myelinating co-culture, ELISA-based signaling assay (ErbB3, Akt, Erk1/2 phosphorylation)","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal loss- and gain-of-function with defined myelination phenotype plus pathway-specific signaling readouts in a single well-controlled study","pmids":["27658374"],"is_preprint":false},{"year":2016,"finding":"NECL1/CADM3-coated PLGA surfaces enhance Schwann cell adhesion and proliferation, and NECL1-coated PLGA conduits implanted to bridge sciatic nerve defects improve Schwann cell aggregation and functional nerve regeneration in vivo, demonstrating that CADM3 on axon surfaces mediates Schwann cell adhesion.","method":"In vitro cell culture on coated surfaces, in vivo sciatic nerve repair model, MTT, RT-PCR, immunohistochemistry","journal":"Materials science & engineering. C","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro and in vivo functional assays with defined cellular readouts but single lab and indirect mechanistic inference","pmids":["27772714"],"is_preprint":false},{"year":2021,"finding":"Genetic ablation of all three axonal Cadms (Cadm1, Cadm2, Cadm3) in mice phenocopies the Cadm4-null abnormalities (aberrant Caspr and Kv1 channel distribution). Double knockout of Cadm3 with Cadm2 or Cadm1 also replicates the Cadm4-null phenotype, but Cadm1/Cadm2 double KO does not. Cadm3 heterozygosity combined with loss of the other two Cadms causes detectable defects, establishing Cadm3 as the primary axonal ligand for glial Cadm4 with partial functional redundancy from Cadm1 and Cadm2.","method":"Genetic epistasis — multiple mouse knockout combinations, immunofluorescence for Caspr and Kv1.2 channel distribution","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic epistasis with multiple mutant combinations in vivo, rigorous hierarchical analysis establishing pathway position","pmids":["33397712"],"is_preprint":false},{"year":2021,"finding":"A dominant missense variant in CADM3 (Tyr172Cys) causes autosomal dominant axonal CMT2. Mass spectrometry detected a novel disulfide bond in the mutant protein. The mutant CADM3 is retained in the endoplasmic reticulum with reduced cell surface expression. STORM imaging revealed decreased co-localization of mutant CADM3 with CADM4 at intercellular contact sites. Cadm3Y170C knock-in mice show normal nerve conduction but abnormal distribution of Kv1.2 channels and Caspr along myelinated axons.","method":"High-resolution mass spectrometry, immunofluorescence/STORM imaging, ER retention assay, knock-in mouse model with axonal organization analysis","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MS, STORM, mouse model, cell surface expression assay) establishing molecular mechanism of pathogenic variant","pmids":["33889941"],"is_preprint":false},{"year":2022,"finding":"SynCAM3/CADM3 knockout mice subjected to spinal cord injury show reduced astrocytic scar formation compared to wild-type, with prevention of reactive astrocyte-to-scar-forming astrocyte transformation and improved ECM reconstitution, indicating CADM3 promotes glial scar formation after CNS injury.","method":"SynCAM3 KO mouse model, single-cell RNA sequencing, qRT-PCR, immunohistochemistry","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo KO with defined cellular phenotype and transcriptomic support, single lab","pmids":["35682897"],"is_preprint":false},{"year":2023,"finding":"A second pathogenic CADM3 variant (Gly368Cys) causes dominant axonal CMT2. Functional analysis showed significantly decreased CADM3-Gly368Cys protein levels at the cell membrane and major predicted structural changes, consistent with the disease mechanism of reduced surface expression established for the Tyr172Cys variant.","method":"Whole exome sequencing, cell membrane fractionation/Western blot, structural prediction","journal":"Brain communications","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, membrane fractionation with structural prediction; partial functional follow-up extending the Tyr172Cys mechanism","pmids":["38074074"],"is_preprint":false},{"year":2024,"finding":"Necl-1/CADM3 is localized at S- and S/M-opsin-containing cones and at dendrites of type 4 OFF cone bipolar cells in mouse retina. Necl-1 knockout mice show dislocated cone-to-type 4 OFF CBC synapses, abnormal horizontal cell distribution, mislocalized AMPA receptors, and aberrant short-wavelength signal transmission rescued by AMPA receptor potentiation, establishing CADM3 as required for cone synapse formation mediating OFF pathways.","method":"Immunofluorescence localization, Necl-1 KO mouse analysis, electroretinography, optokinetic response testing, AMPA receptor potentiator rescue experiment","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo KO with multiple orthogonal phenotypic readouts (synaptic morphology, physiology, pharmacological rescue) in a single focused study","pmids":["38623325"],"is_preprint":false},{"year":2025,"finding":"Necl1/CADM3 deficiency in rats causes prefrontal cortex-specific noradrenergic dysfunction: norepinephrine depletion, dendritic spine loss, and upregulation of adrenergic receptor α2A (Adra2a). Adra2a antagonism (mirtazapine) rescues depressive phenotypes in KO rats; prefrontal-targeted Necl1 reconstitution rescues depressive behavior and normalizes Adra2a expression, establishing Necl1 as a synaptic-noradrenergic integrator in emotional processing.","method":"Constitutive KO in rats and mice, pharmacological rescue (mirtazapine, reboxetine), AAV-mediated regional reconstitution, norepinephrine measurement, dendritic spine analysis, adrenergic receptor expression analysis","journal":"Journal of affective disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO, pharmacological rescue, regional reconstitution) in two species, single lab","pmids":["41308882"],"is_preprint":false}],"current_model":"CADM3 (Necl-1/SynCAM3) is a neural-tissue-specific, Ca2+-independent immunoglobulin superfamily cell adhesion molecule whose V-domain mediates homophilic trans-dimerization (Phe82-dependent) and heterophilic binding to Necl-2, nectin-1, nectin-3, and especially glial Cadm4; its cytoplasmic tail binds MAGUK proteins (Dlg3, Pals2, CASK) but not afadin; at peripheral myelinated axons it serves as the primary ligand for glial Cadm4 and negatively regulates Schwann cell myelination by selectively suppressing PI3K/Akt (but not Mek/Erk) signaling; in the CNS it is required for cone synapse formation in the retina, promotes glial scar formation after spinal cord injury, and modulates prefrontal noradrenergic tone to gate emotional behavior; pathogenic dominant variants (Tyr172Cys, Gly368Cys) cause axonal Charcot-Marie-Tooth disease by forming aberrant disulfide bonds, triggering ER retention, reducing surface expression, and impairing Cadm4 co-localization at axon-glia contact sites; in glioma, CADM3 expression is silenced by histone deacetylation via an Sp1/HDAC1 mechanism and its re-expression induces cell cycle arrest, inhibits migration/invasion, and promotes astrocytic differentiation."},"narrative":{"mechanistic_narrative":"CADM3 (Necl-1/SynCAM3) is a neural immunoglobulin-superfamily cell adhesion molecule that mediates Ca2+-independent intercellular adhesion at axon-glia and synaptic contact sites [PMID:15741237]. Its N-terminal Ig-like V domain is sufficient for homophilic trans-dimerization, with Phe82 identified as a key adhesion residue from the dimeric crystal structure [PMID:16467305], and the same ectodomain engages heterophilic partners including Necl-2, nectin-1, nectin-3, and the glial partner Cadm4 [PMID:15741237, PMID:21456004]. Its cytoplasmic tail recruits L27-domain MAGUK proteins (Dlg3, Pals2, CASK) but not afadin [PMID:15741237]. At peripheral myelinated axons CADM3 is the primary axonal ligand for glial Cadm4, organizing Caspr and Kv1 channel distribution with partial redundancy from Cadm1 and Cadm2 [PMID:33397712], and it negatively regulates Schwann cell myelination by selectively suppressing ErbB3-PI3K/Akt signaling without affecting Mek/Erk [PMID:27658374]. In the CNS, CADM3 is required for cone-to-bipolar-cell synapse formation in the retina [PMID:38623325], promotes astrocytic scar formation after spinal cord injury [PMID:35682897], and modulates prefrontal noradrenergic tone to gate emotional behavior [PMID:41308882]. Dominant missense variants (Tyr172Cys, Gly368Cys) cause axonal Charcot-Marie-Tooth disease by introducing aberrant disulfide bonds that drive ER retention, reduce cell-surface expression, and impair Cadm4 co-localization at axon-glia contacts [PMID:33889941, PMID:38074074]. In glioma, CADM3 is epigenetically silenced through an Sp1/HDAC1 histone-deacetylation mechanism, and its re-expression induces cell cycle arrest, suppresses migration and invasion, and promotes astrocytic differentiation [PMID:19062177, PMID:20078932].","teleology":[{"year":2005,"claim":"Established that CADM3 is an adhesion molecule with defined homophilic and heterophilic binding partners and a MAGUK-linked cytoplasmic tail, defining its molecular identity and intracellular scaffold.","evidence":"Cell-cell adhesion assays, Co-IP, and domain mapping defining homophilic adhesion, heterophilic binding to Necl-2/nectin-1/nectin-3, and L27-MAGUK binding (Dlg3, Pals2, CASK) but not afadin","pmids":["15741237"],"confidence":"High","gaps":["Functional consequence of MAGUK binding not tested","Affinity hierarchy among heterophilic partners not quantified"]},{"year":2005,"claim":"Localized CADM3 to non-junctional axon, synaptic, and glial contact sites, predicting roles in synapse formation, axon bundling, and myelination.","evidence":"Immunofluorescence and immunoelectron microscopy of nerve terminals, axons, and myelinated axons","pmids":["15741237"],"confidence":"High","gaps":["Localization is descriptive; functional roles not directly tested"]},{"year":2006,"claim":"Defined the structural basis of adhesion, showing the V domain alone drives dimerization and identifying Phe82 as essential, providing a molecular handle for adhesion function.","evidence":"X-ray crystallography at 2.4 A, size-exclusion chromatography, cross-linking, and site-directed mutagenesis","pmids":["16467305"],"confidence":"High","gaps":["Structure of heterophilic complexes (e.g. with Cadm4) not solved","In vivo consequence of Phe82 mutation untested"]},{"year":2008,"claim":"Showed CADM3 is silenced in glioma and acts as a growth/proliferation restraint, framing it as a candidate tumor suppressor in glial tumors.","evidence":"Re-expression in T98G glioma cells with growth curves, flow cytometry, and apoptosis assays; co-culture and synaptosome synapse-formation assays","pmids":["18686605","18686604"],"confidence":"Medium","gaps":["Single cell line for tumor phenotype","Pathway linking re-expression to arrest/apoptosis not defined"]},{"year":2009,"claim":"Identified the epigenetic mechanism of CADM3 silencing in glioma and confirmed tumor-suppressive consequences, linking an Sp1/HDAC1 switch to loss of expression.","evidence":"Luciferase reporter, ChIP, Co-IP, bisulfite sequencing, HDAC assay, and xenograft showing HDAC-mediated silencing, Sp1/HDAC1-to-Sp1/p300 switch, and growth suppression; plus migration/invasion and GFAP differentiation assays","pmids":["19062177","20078932"],"confidence":"High","gaps":["Upstream trigger of HDAC1 recruitment unknown","Differentiation readout limited to GFAP"]},{"year":2016,"claim":"Placed CADM3 in the myelination pathway as a negative regulator acting through pathway-selective signaling suppression, resolving how axonal adhesion tunes Schwann cell behavior.","evidence":"Reciprocal shRNA knockdown and overexpression in DRG/Schwann co-cultures with ELISA-based ErbB3/Akt/Erk phosphorylation readouts; PLGA-coating adhesion and sciatic nerve repair models","pmids":["27658374","27772714"],"confidence":"High","gaps":["Mechanism by which the ectodomain blocks ErbB3 activation unresolved","Selectivity for PI3K/Akt over Mek/Erk not mechanistically explained"]},{"year":2021,"claim":"Established CADM3 as the primary axonal ligand for glial Cadm4 with redundancy from Cadm1/Cadm2, fixing its position in the axon-glia adhesion hierarchy.","evidence":"Systematic mouse knockout combinations with immunofluorescence for Caspr and Kv1.2 distribution","pmids":["33397712"],"confidence":"High","gaps":["Molecular basis of preferential Cadm3-Cadm4 binding not structurally defined","Quantitative contribution of each paralog unresolved"]},{"year":2021,"claim":"Demonstrated that a dominant CMT2 variant acts through aberrant disulfide bonding, ER retention, and loss of Cadm4 co-localization, defining the disease mechanism.","evidence":"Mass spectrometry, STORM imaging, ER retention/surface expression assays, and Cadm3Y170C knock-in mice with Kv1.2/Caspr analysis","pmids":["33889941"],"confidence":"High","gaps":["Knock-in mice showed normal conduction, leaving genotype-phenotype gap unresolved","Whether loss-of-function or dominant-negative dominates not separated"]},{"year":2022,"claim":"Revealed a CNS injury role, showing CADM3 promotes reactive-to-scar astrocyte transformation and glial scar formation.","evidence":"SynCAM3 KO mouse spinal cord injury model with single-cell RNA sequencing, qRT-PCR, and immunohistochemistry","pmids":["35682897"],"confidence":"Medium","gaps":["Direct adhesion partner driving astrocyte transformation not identified","Single lab"]},{"year":2023,"claim":"Extended the CMT2 mechanism to a second variant, generalizing reduced surface expression via cysteine-introducing mutations as the pathogenic principle.","evidence":"Whole exome sequencing, membrane fractionation/Western blot, and structural prediction for Gly368Cys","pmids":["38074074"],"confidence":"Medium","gaps":["No in vivo model for Gly368Cys","Structural change inferred from prediction, not solved"]},{"year":2024,"claim":"Demonstrated a CNS synaptic requirement, showing CADM3 is needed for cone-to-OFF-bipolar synapse formation and AMPA receptor positioning in the retina.","evidence":"Immunofluorescence localization, Necl-1 KO mouse analysis, electroretinography, optokinetic testing, and AMPA receptor potentiator rescue","pmids":["38623325"],"confidence":"High","gaps":["Heterophilic partner in the retinal synapse not identified","Link between adhesion and AMPA receptor localization mechanistically unresolved"]},{"year":2025,"claim":"Linked CADM3 to prefrontal noradrenergic regulation of emotional behavior, identifying Adra2a as a downstream effector amenable to pharmacological and genetic rescue.","evidence":"Constitutive KO in rats and mice, mirtazapine/reboxetine pharmacological rescue, AAV regional reconstitution, norepinephrine and dendritic spine measurements","pmids":["41308882"],"confidence":"Medium","gaps":["Mechanism connecting CADM3 adhesion to Adra2a expression unknown","Single lab"]},{"year":null,"claim":"How CADM3 ectodomain engagement is mechanistically transduced into divergent intracellular outcomes — PI3K/Akt suppression in Schwann cells, AMPA receptor positioning in retina, and noradrenergic tone in cortex — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified signaling model links adhesion to downstream effectors","MAGUK scaffold function not tied to any in vivo phenotype","Structural basis of Cadm3-Cadm4 heterophilic binding undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,2,7,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,11]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,10,14]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,14,15]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,13]}],"complexes":[],"partners":["CADM4","CADM1","CADM2","NECTIN1","NECTIN3","DLG3","CASK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N126","full_name":"Cell adhesion molecule 3","aliases":["Brain immunoglobulin receptor","Immunoglobulin superfamily member 4B","IgSF4B","Nectin-like protein 1","NECL-1","Synaptic cell adhesion molecule 3","SynCAM3","TSLC1-like protein 1","TSLL1"],"length_aa":398,"mass_kda":43.3,"function":"Involved in cell-cell adhesion. Has both calcium-independent homophilic cell-cell adhesion activity and calcium-independent heterophilic cell-cell adhesion activity with IGSF4, NECTIN1 and NECTIN3. Interaction with EPB41L1 may regulate structure or function of cell-cell junctions (By similarity)","subcellular_location":"Cell membrane; Cell junction","url":"https://www.uniprot.org/uniprotkb/Q8N126/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CADM3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CADM3","total_profiled":1310},"omim":[{"mim_id":"619519","title":"CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2FF; CMT2FF","url":"https://www.omim.org/entry/619519"},{"mim_id":"609743","title":"CELL ADHESION MOLECULE 3; CADM3","url":"https://www.omim.org/entry/609743"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":323.0}],"url":"https://www.proteinatlas.org/search/CADM3"},"hgnc":{"alias_symbol":["BIgR","FLJ10698","TSLL1","NECL1","SynCAM3","Necl-1"],"prev_symbol":["IGSF4B"]},"alphafold":{"accession":"Q8N126","domains":[{"cath_id":"2.60.40.10","chopping":"35-128","consensus_level":"high","plddt":96.6836,"start":35,"end":128},{"cath_id":"2.60.40.10","chopping":"135-228","consensus_level":"high","plddt":94.9455,"start":135,"end":228},{"cath_id":"2.60.40.10","chopping":"233-315","consensus_level":"high","plddt":87.9882,"start":233,"end":315}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N126","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N126-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N126-F1-predicted_aligned_error_v6.png","plddt_mean":84.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CADM3","jax_strain_url":"https://www.jax.org/strain/search?query=CADM3"},"sequence":{"accession":"Q8N126","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N126.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N126/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N126"}},"corpus_meta":[{"pmid":"15741237","id":"PMC_15741237","title":"Nectin-like molecule-1/TSLL1/SynCAM3: a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule localizing at non-junctional contact sites of presynaptic nerve terminals, axons and glia cell processes.","date":"2005","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15741237","citation_count":110,"is_preprint":false},{"pmid":"21632538","id":"PMC_21632538","title":"Plant pathogenic bacteria utilize biofilm growth-associated repressor (BigR), a novel winged-helix redox switch, to control hydrogen sulfide detoxification under hypoxia.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21632538","citation_count":67,"is_preprint":false},{"pmid":"11536053","id":"PMC_11536053","title":"Isolation of the TSLL1 and TSLL2 genes, members of the tumor suppressor TSLC1 gene family encoding transmembrane 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Its C-terminal cytoplasmic region binds membrane-associated guanylate kinase (MAGUK) subfamily members containing the L27 domain (Dlg3, Pals2, and CASK), but does not bind afadin.\",\n      \"method\": \"Cell-cell adhesion assays, co-immunoprecipitation, domain mapping\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal binding assays (adhesion assay, Co-IP, domain mapping) in a single focused study; findings replicated conceptually by subsequent structural and functional studies\",\n      \"pmids\": [\"15741237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Necl-1/CADM3 localizes at non-junctional contact sites of presynaptic nerve terminals, axons, and glial cell processes (axon bundles and myelinated axons) as determined by immunofluorescence and immunoelectron microscopy, consistent with roles in synapse formation, axon bundling, and myelination.\",\n      \"method\": \"Immunofluorescence microscopy, immunoelectron microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct immunoelectron microscopy localization with high spatial resolution, replicated by multiple subsequent studies\",\n      \"pmids\": [\"15741237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The N-terminal Ig-like V domain of Necl-1/CADM3 is sufficient for homophilic interaction; the protein crystallizes as a dimer confirmed by size-exclusion chromatography and chemical cross-linking. Mutagenesis identified Phe82 as a key residue for adhesion activity.\",\n      \"method\": \"X-ray crystallography (2.4 Å resolution), size-exclusion chromatography, chemical cross-linking, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with mutagenesis and biochemical validation in one rigorous study\",\n      \"pmids\": [\"16467305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss of NECL1/CADM3 expression in glioma is caused at least partly by histone deacetylation (not CpG methylation). HDAC inhibitor TSA reactivates NECL1 expression. Sp1 binds HDAC1 at the NECL1 promoter in untreated glioma cells, and switches to binding p300/CBP after TSA treatment. Re-expression of NECL1 in glioma cells induces cell cycle arrest and suppresses proliferation in vitro and tumor growth in vivo.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), DNA bisulfite sequencing, HDAC activity assay, xenograft model\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, reporter assay, in vivo model) in a single study establishing the epigenetic regulatory mechanism\",\n      \"pmids\": [\"19062177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NECL1/CADM3 expression in glioma cells inhibits migration and invasion (scratch and Transwell assays), reduces extracellular metalloproteinase activities, and promotes potential differentiation toward an astrocyte phenotype with upregulation of GFAP.\",\n      \"method\": \"Scratch assay, Transwell assay, metalloproteinase activity measurement, Western blot for GFAP\",\n      \"journal\": \"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, standard cellular assays with functional readouts but limited mechanistic depth\",\n      \"pmids\": [\"20078932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Re-expression of NECL1/CADM3 in the NECL1-silent T98G glioma cell line decreases cell growth rate and increases apoptosis, establishing a role in restraining glioma cell proliferation.\",\n      \"method\": \"Cell growth curve, flow cytometry, Hoechst staining\",\n      \"journal\": \"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, loss/gain-of-function with defined cellular phenotype but limited mechanistic pathway placement\",\n      \"pmids\": [\"18686605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Overexpression of Necl1/CADM3 in HEK293 cells induces synapse formation when co-cultured with neurons. Ectopic expression of Necl1 in primary neurons increases synapse density. Necl1 partially localizes to synaptosomes.\",\n      \"method\": \"Co-culture synapse formation assay, immunofluorescence, Western blot, synaptosome fractionation\",\n      \"journal\": \"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gain-of-function with functional synaptic readout but limited orthogonal validation\",\n      \"pmids\": [\"18686604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Zebrafish cadm3 and cadm2a bind heterophilically: in vitro binding assays show cadm3 preferentially binds cadm4, while cadm2a preferentially binds cadm1, mirroring tetrapod binding preferences.\",\n      \"method\": \"In vitro binding assay with subtype-specific antibodies\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding assay in vitro, single lab, single method\",\n      \"pmids\": [\"21456004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"shRNA-mediated knockdown of axonal Cadm3 promotes Schwann cell myelination in DRG neuron/Schwann cell co-cultures, while overexpression of Cadm3 nearly abolishes myelin segment formation. SCG neurons (which do not support myelination) express higher Cadm3 than DRG neurons; Cadm3 knockdown in SCG neurons enables myelination. The extracellular domain of Cadm3 interferes dose-dependently with activation of ErbB3 and the PI3K/Akt pro-myelinating pathway but does not affect the Mek/Erk1/2 pathway.\",\n      \"method\": \"shRNA knockdown, overexpression in vitro myelinating co-culture, ELISA-based signaling assay (ErbB3, Akt, Erk1/2 phosphorylation)\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss- and gain-of-function with defined myelination phenotype plus pathway-specific signaling readouts in a single well-controlled study\",\n      \"pmids\": [\"27658374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NECL1/CADM3-coated PLGA surfaces enhance Schwann cell adhesion and proliferation, and NECL1-coated PLGA conduits implanted to bridge sciatic nerve defects improve Schwann cell aggregation and functional nerve regeneration in vivo, demonstrating that CADM3 on axon surfaces mediates Schwann cell adhesion.\",\n      \"method\": \"In vitro cell culture on coated surfaces, in vivo sciatic nerve repair model, MTT, RT-PCR, immunohistochemistry\",\n      \"journal\": \"Materials science & engineering. C\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro and in vivo functional assays with defined cellular readouts but single lab and indirect mechanistic inference\",\n      \"pmids\": [\"27772714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic ablation of all three axonal Cadms (Cadm1, Cadm2, Cadm3) in mice phenocopies the Cadm4-null abnormalities (aberrant Caspr and Kv1 channel distribution). Double knockout of Cadm3 with Cadm2 or Cadm1 also replicates the Cadm4-null phenotype, but Cadm1/Cadm2 double KO does not. Cadm3 heterozygosity combined with loss of the other two Cadms causes detectable defects, establishing Cadm3 as the primary axonal ligand for glial Cadm4 with partial functional redundancy from Cadm1 and Cadm2.\",\n      \"method\": \"Genetic epistasis — multiple mouse knockout combinations, immunofluorescence for Caspr and Kv1.2 channel distribution\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic epistasis with multiple mutant combinations in vivo, rigorous hierarchical analysis establishing pathway position\",\n      \"pmids\": [\"33397712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A dominant missense variant in CADM3 (Tyr172Cys) causes autosomal dominant axonal CMT2. Mass spectrometry detected a novel disulfide bond in the mutant protein. The mutant CADM3 is retained in the endoplasmic reticulum with reduced cell surface expression. STORM imaging revealed decreased co-localization of mutant CADM3 with CADM4 at intercellular contact sites. Cadm3Y170C knock-in mice show normal nerve conduction but abnormal distribution of Kv1.2 channels and Caspr along myelinated axons.\",\n      \"method\": \"High-resolution mass spectrometry, immunofluorescence/STORM imaging, ER retention assay, knock-in mouse model with axonal organization analysis\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MS, STORM, mouse model, cell surface expression assay) establishing molecular mechanism of pathogenic variant\",\n      \"pmids\": [\"33889941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SynCAM3/CADM3 knockout mice subjected to spinal cord injury show reduced astrocytic scar formation compared to wild-type, with prevention of reactive astrocyte-to-scar-forming astrocyte transformation and improved ECM reconstitution, indicating CADM3 promotes glial scar formation after CNS injury.\",\n      \"method\": \"SynCAM3 KO mouse model, single-cell RNA sequencing, qRT-PCR, immunohistochemistry\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo KO with defined cellular phenotype and transcriptomic support, single lab\",\n      \"pmids\": [\"35682897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A second pathogenic CADM3 variant (Gly368Cys) causes dominant axonal CMT2. Functional analysis showed significantly decreased CADM3-Gly368Cys protein levels at the cell membrane and major predicted structural changes, consistent with the disease mechanism of reduced surface expression established for the Tyr172Cys variant.\",\n      \"method\": \"Whole exome sequencing, cell membrane fractionation/Western blot, structural prediction\",\n      \"journal\": \"Brain communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, membrane fractionation with structural prediction; partial functional follow-up extending the Tyr172Cys mechanism\",\n      \"pmids\": [\"38074074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Necl-1/CADM3 is localized at S- and S/M-opsin-containing cones and at dendrites of type 4 OFF cone bipolar cells in mouse retina. Necl-1 knockout mice show dislocated cone-to-type 4 OFF CBC synapses, abnormal horizontal cell distribution, mislocalized AMPA receptors, and aberrant short-wavelength signal transmission rescued by AMPA receptor potentiation, establishing CADM3 as required for cone synapse formation mediating OFF pathways.\",\n      \"method\": \"Immunofluorescence localization, Necl-1 KO mouse analysis, electroretinography, optokinetic response testing, AMPA receptor potentiator rescue experiment\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with multiple orthogonal phenotypic readouts (synaptic morphology, physiology, pharmacological rescue) in a single focused study\",\n      \"pmids\": [\"38623325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Necl1/CADM3 deficiency in rats causes prefrontal cortex-specific noradrenergic dysfunction: norepinephrine depletion, dendritic spine loss, and upregulation of adrenergic receptor α2A (Adra2a). Adra2a antagonism (mirtazapine) rescues depressive phenotypes in KO rats; prefrontal-targeted Necl1 reconstitution rescues depressive behavior and normalizes Adra2a expression, establishing Necl1 as a synaptic-noradrenergic integrator in emotional processing.\",\n      \"method\": \"Constitutive KO in rats and mice, pharmacological rescue (mirtazapine, reboxetine), AAV-mediated regional reconstitution, norepinephrine measurement, dendritic spine analysis, adrenergic receptor expression analysis\",\n      \"journal\": \"Journal of affective disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO, pharmacological rescue, regional reconstitution) in two species, single lab\",\n      \"pmids\": [\"41308882\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CADM3 (Necl-1/SynCAM3) is a neural-tissue-specific, Ca2+-independent immunoglobulin superfamily cell adhesion molecule whose V-domain mediates homophilic trans-dimerization (Phe82-dependent) and heterophilic binding to Necl-2, nectin-1, nectin-3, and especially glial Cadm4; its cytoplasmic tail binds MAGUK proteins (Dlg3, Pals2, CASK) but not afadin; at peripheral myelinated axons it serves as the primary ligand for glial Cadm4 and negatively regulates Schwann cell myelination by selectively suppressing PI3K/Akt (but not Mek/Erk) signaling; in the CNS it is required for cone synapse formation in the retina, promotes glial scar formation after spinal cord injury, and modulates prefrontal noradrenergic tone to gate emotional behavior; pathogenic dominant variants (Tyr172Cys, Gly368Cys) cause axonal Charcot-Marie-Tooth disease by forming aberrant disulfide bonds, triggering ER retention, reducing surface expression, and impairing Cadm4 co-localization at axon-glia contact sites; in glioma, CADM3 expression is silenced by histone deacetylation via an Sp1/HDAC1 mechanism and its re-expression induces cell cycle arrest, inhibits migration/invasion, and promotes astrocytic differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CADM3 (Necl-1/SynCAM3) is a neural immunoglobulin-superfamily cell adhesion molecule that mediates Ca2+-independent intercellular adhesion at axon-glia and synaptic contact sites [#0, #1]. Its N-terminal Ig-like V domain is sufficient for homophilic trans-dimerization, with Phe82 identified as a key adhesion residue from the dimeric crystal structure [#2], and the same ectodomain engages heterophilic partners including Necl-2, nectin-1, nectin-3, and the glial partner Cadm4 [#0, #7]. Its cytoplasmic tail recruits L27-domain MAGUK proteins (Dlg3, Pals2, CASK) but not afadin [#0]. At peripheral myelinated axons CADM3 is the primary axonal ligand for glial Cadm4, organizing Caspr and Kv1 channel distribution with partial redundancy from Cadm1 and Cadm2 [#10], and it negatively regulates Schwann cell myelination by selectively suppressing ErbB3-PI3K/Akt signaling without affecting Mek/Erk [#8]. In the CNS, CADM3 is required for cone-to-bipolar-cell synapse formation in the retina [#14], promotes astrocytic scar formation after spinal cord injury [#12], and modulates prefrontal noradrenergic tone to gate emotional behavior [#15]. Dominant missense variants (Tyr172Cys, Gly368Cys) cause axonal Charcot-Marie-Tooth disease by introducing aberrant disulfide bonds that drive ER retention, reduce cell-surface expression, and impair Cadm4 co-localization at axon-glia contacts [#11, #13]. In glioma, CADM3 is epigenetically silenced through an Sp1/HDAC1 histone-deacetylation mechanism, and its re-expression induces cell cycle arrest, suppresses migration and invasion, and promotes astrocytic differentiation [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that CADM3 is an adhesion molecule with defined homophilic and heterophilic binding partners and a MAGUK-linked cytoplasmic tail, defining its molecular identity and intracellular scaffold.\",\n      \"evidence\": \"Cell-cell adhesion assays, Co-IP, and domain mapping defining homophilic adhesion, heterophilic binding to Necl-2/nectin-1/nectin-3, and L27-MAGUK binding (Dlg3, Pals2, CASK) but not afadin\",\n      \"pmids\": [\"15741237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MAGUK binding not tested\", \"Affinity hierarchy among heterophilic partners not quantified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Localized CADM3 to non-junctional axon, synaptic, and glial contact sites, predicting roles in synapse formation, axon bundling, and myelination.\",\n      \"evidence\": \"Immunofluorescence and immunoelectron microscopy of nerve terminals, axons, and myelinated axons\",\n      \"pmids\": [\"15741237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Localization is descriptive; functional roles not directly tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the structural basis of adhesion, showing the V domain alone drives dimerization and identifying Phe82 as essential, providing a molecular handle for adhesion function.\",\n      \"evidence\": \"X-ray crystallography at 2.4 A, size-exclusion chromatography, cross-linking, and site-directed mutagenesis\",\n      \"pmids\": [\"16467305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of heterophilic complexes (e.g. with Cadm4) not solved\", \"In vivo consequence of Phe82 mutation untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed CADM3 is silenced in glioma and acts as a growth/proliferation restraint, framing it as a candidate tumor suppressor in glial tumors.\",\n      \"evidence\": \"Re-expression in T98G glioma cells with growth curves, flow cytometry, and apoptosis assays; co-culture and synaptosome synapse-formation assays\",\n      \"pmids\": [\"18686605\", \"18686604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line for tumor phenotype\", \"Pathway linking re-expression to arrest/apoptosis not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the epigenetic mechanism of CADM3 silencing in glioma and confirmed tumor-suppressive consequences, linking an Sp1/HDAC1 switch to loss of expression.\",\n      \"evidence\": \"Luciferase reporter, ChIP, Co-IP, bisulfite sequencing, HDAC assay, and xenograft showing HDAC-mediated silencing, Sp1/HDAC1-to-Sp1/p300 switch, and growth suppression; plus migration/invasion and GFAP differentiation assays\",\n      \"pmids\": [\"19062177\", \"20078932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream trigger of HDAC1 recruitment unknown\", \"Differentiation readout limited to GFAP\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed CADM3 in the myelination pathway as a negative regulator acting through pathway-selective signaling suppression, resolving how axonal adhesion tunes Schwann cell behavior.\",\n      \"evidence\": \"Reciprocal shRNA knockdown and overexpression in DRG/Schwann co-cultures with ELISA-based ErbB3/Akt/Erk phosphorylation readouts; PLGA-coating adhesion and sciatic nerve repair models\",\n      \"pmids\": [\"27658374\", \"27772714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the ectodomain blocks ErbB3 activation unresolved\", \"Selectivity for PI3K/Akt over Mek/Erk not mechanistically explained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CADM3 as the primary axonal ligand for glial Cadm4 with redundancy from Cadm1/Cadm2, fixing its position in the axon-glia adhesion hierarchy.\",\n      \"evidence\": \"Systematic mouse knockout combinations with immunofluorescence for Caspr and Kv1.2 distribution\",\n      \"pmids\": [\"33397712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of preferential Cadm3-Cadm4 binding not structurally defined\", \"Quantitative contribution of each paralog unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that a dominant CMT2 variant acts through aberrant disulfide bonding, ER retention, and loss of Cadm4 co-localization, defining the disease mechanism.\",\n      \"evidence\": \"Mass spectrometry, STORM imaging, ER retention/surface expression assays, and Cadm3Y170C knock-in mice with Kv1.2/Caspr analysis\",\n      \"pmids\": [\"33889941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Knock-in mice showed normal conduction, leaving genotype-phenotype gap unresolved\", \"Whether loss-of-function or dominant-negative dominates not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a CNS injury role, showing CADM3 promotes reactive-to-scar astrocyte transformation and glial scar formation.\",\n      \"evidence\": \"SynCAM3 KO mouse spinal cord injury model with single-cell RNA sequencing, qRT-PCR, and immunohistochemistry\",\n      \"pmids\": [\"35682897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct adhesion partner driving astrocyte transformation not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the CMT2 mechanism to a second variant, generalizing reduced surface expression via cysteine-introducing mutations as the pathogenic principle.\",\n      \"evidence\": \"Whole exome sequencing, membrane fractionation/Western blot, and structural prediction for Gly368Cys\",\n      \"pmids\": [\"38074074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo model for Gly368Cys\", \"Structural change inferred from prediction, not solved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a CNS synaptic requirement, showing CADM3 is needed for cone-to-OFF-bipolar synapse formation and AMPA receptor positioning in the retina.\",\n      \"evidence\": \"Immunofluorescence localization, Necl-1 KO mouse analysis, electroretinography, optokinetic testing, and AMPA receptor potentiator rescue\",\n      \"pmids\": [\"38623325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heterophilic partner in the retinal synapse not identified\", \"Link between adhesion and AMPA receptor localization mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked CADM3 to prefrontal noradrenergic regulation of emotional behavior, identifying Adra2a as a downstream effector amenable to pharmacological and genetic rescue.\",\n      \"evidence\": \"Constitutive KO in rats and mice, mirtazapine/reboxetine pharmacological rescue, AAV regional reconstitution, norepinephrine and dendritic spine measurements\",\n      \"pmids\": [\"41308882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CADM3 adhesion to Adra2a expression unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CADM3 ectodomain engagement is mechanistically transduced into divergent intracellular outcomes — PI3K/Akt suppression in Schwann cells, AMPA receptor positioning in retina, and noradrenergic tone in cortex — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified signaling model links adhesion to downstream effectors\", \"MAGUK scaffold function not tied to any in vivo phenotype\", \"Structural basis of Cadm3-Cadm4 heterophilic binding undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 2, 7, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 10, 14]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 14, 15]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CADM4\", \"CADM1\", \"CADM2\", \"NECTIN1\", \"NECTIN3\", \"DLG3\", \"CASK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}