{"gene":"CADM3","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2005,"finding":"Necl-1/CADM3 exhibits Ca2+-independent homophilic cell-cell adhesion activity and heterophilic adhesion with Necl-2/SynCAM1, nectin-1 and nectin-3. Its C-terminal cytoplasmic region binds membrane-associated guanylate kinase (MAGUK) subfamily members containing the L27 domain, including Dlg3, Pals2 and CASK, but does not bind afadin.","method":"Cell-cell adhesion assays, co-immunoprecipitation, immunofluorescence and immunoelectron microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (adhesion assays, co-IP, immunoEM) in a single foundational study with 110 citations","pmids":["15741237"],"is_preprint":false},{"year":2006,"finding":"The N-terminal Ig-like V domain of Necl-1/CADM3 is sufficient for homophilic interaction, crystallizes as a dimer confirmed by size-exclusion chromatography and chemical cross-linking, and Phe82 is a key residue for adhesion activity.","method":"Crystal structure at 2.4 Å, size-exclusion chromatography, chemical cross-linking, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and biochemical validation","pmids":["16467305"],"is_preprint":false},{"year":2009,"finding":"Re-expression of NECL1/CADM3 in glioma cells represses proliferation by inducing cell cycle arrest and reduces tumor growth in vivo; loss of NECL1 expression in glioma is caused at least partly by histone deacetylation, mediated through Sp1 binding to either HDAC1 (in untreated cells) or p300/CBP (after TSA treatment) at the NECL1 promoter.","method":"Cell proliferation assays, flow cytometry, nude mouse xenograft, luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, HDAC activity assay","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, co-IP, luciferase reporter, in vivo xenograft) in a single study","pmids":["19062177"],"is_preprint":false},{"year":2009,"finding":"Necl1/CADM3 expressed on Schwann cells (detected via Necl1-Fc affinity reagent) allows FACS-based isolation of myelination-competent Schwann cells, demonstrating that Necl1 is a surface marker mediating axon-Schwann cell contact.","method":"FACS-based cell isolation using Necl1-Fc fusion protein, myelinating co-culture assay","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional demonstration of Necl1 surface localization on Schwann cells with functional myelination readout, single study","pmids":["19125407"],"is_preprint":false},{"year":2011,"finding":"In vitro binding assays with zebrafish cadm3 show that cadm3 binds heterophilically and preferentially to cadm4 (the glial partner), consistent with its role in axon-glia contact; cadm3 and cadm2a show largely non-overlapping expression in developing retina and spinal cord.","method":"In vitro binding assays, subtype-specific antibodies, immunohistochemistry","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vitro binding assay with single study; ortholog in zebrafish","pmids":["21456004"],"is_preprint":false},{"year":2016,"finding":"Axonal Cadm3 negatively regulates Schwann cell myelination: shRNA knockdown of Cadm3 in DRG neurons promotes myelination, while overexpression almost completely prevents myelin segment formation. Cadm3 extracellular domain interferes dose-dependently with activation of ErbB3 and the pro-myelinating PI3K/Akt pathway but not the Mek/Erk1/2 pathway.","method":"shRNA knockdown, overexpression in DRG neuron/Schwann cell myelinating co-culture, Western blot for ErbB3/PI3K/Akt/Erk phosphorylation","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic manipulation (KD and OE) with defined pathway readout and selective signaling dissection","pmids":["27658374"],"is_preprint":false},{"year":2021,"finding":"Genetic epistasis in mice shows that Cadm3 is the main axonal ligand for glial Cadm4: triple knockout of Cadm1/2/3 phenocopies Cadm4 null abnormalities (Caspr and Kv1 potassium channel distribution defects); Cadm3 single KO combined with heterozygosity at Cadm1 and Cadm2 also produces defects, establishing a hierarchical adhesion code with Cadm3 as the dominant partner.","method":"Genetic epistasis (single, double, and triple knockout mice), immunofluorescence for Caspr and Kv1.2 distribution","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — rigorous genetic epistasis with multiple allele combinations, replicated phenotype across genotypes","pmids":["33397712"],"is_preprint":false},{"year":2021,"finding":"A CADM3 Tyr172Cys variant causes axonal Charcot-Marie-Tooth disease; the mutation creates a novel disulfide bond altering protein conformation, causes ER retention and reduced cell surface expression, decreases co-localization with CADM4 at intercellular contact sites, and in Cadm3Y170C knock-in mice produces abnormal Kv1.2 channel and Caspr distribution without affecting myelin morphology.","method":"High-resolution mass spectrometry, STORM super-resolution microscopy, cell surface expression assay, Cadm3Y170C knock-in mice, immunofluorescence","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (MS, super-resolution imaging, knock-in mouse model) in a single rigorous study","pmids":["33889941"],"is_preprint":false},{"year":2022,"finding":"SynCAM3/CADM3 deletion in mice reduces glial scar formation after spinal cord injury by preventing transformation of reactive astrocytes into scar-forming astrocytes, resulting in improved functional recovery and ECM reconstitution.","method":"SynCAM3 knockout mice, spinal cord compression injury, single-cell RNA sequencing, qRT-PCR, immunohistochemistry, behavioral assessment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype and functional readout, single study with multiple methods","pmids":["35682897"],"is_preprint":false},{"year":2023,"finding":"A novel CADM3 Gly368Cys variant causes axonal CMT neuropathy with autosomal dominant inheritance; functional analysis shows significantly decreased mutant CADM3 protein levels at the membrane and major predicted structural changes, extending the disease mechanism established for the Tyr172Cys variant.","method":"Whole exome sequencing, Western blot for membrane protein levels, structural prediction analysis","journal":"Brain communications","confidence":"Medium","confidence_rationale":"Tier 3 — cell surface expression assay plus structural prediction; single study, limited experimental methods","pmids":["38074074"],"is_preprint":false},{"year":2024,"finding":"Necl-1/CADM3 localizes at S- and S/M-opsin-containing cones and dendrites of type 4 OFF cone bipolar cells; Necl-1 knockout mice exhibit dislocated cone-to-type 4 OFF CBC synapses, abnormal horizontal cell distribution, dislocated AMPA receptors, and impaired short-wavelength cone signal transmission rescued by an AMPA receptor potentiator, indicating Necl-1 regulates cone synapse formation for OFF pathways.","method":"Immunofluorescence localization, Necl-1 knockout mice, electroretinography, optokinetic response assay, pharmacological rescue with AMPA receptor potentiator","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal functional readouts and pharmacological rescue validation","pmids":["38623325"],"is_preprint":false},{"year":2008,"finding":"Overexpression of Necl1/CADM3 in HEK293 cells induces synapse formation between cocultured 293 cells and neurons, and ectopic expression in primary neurons increases synapse density; Necl1 expression increases during neuronal differentiation and is found in synaptosome fractions.","method":"Overexpression in 293/primary neuron co-culture, immunofluorescence, synaptosome fractionation, Western blot","journal":"Zhongguo yi xue ke xue yuan xue bao","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional overexpression assay with synaptogenic readout plus subcellular fractionation, single study","pmids":["18686604"],"is_preprint":false},{"year":2009,"finding":"Restoration of NECL1/CADM3 in NECL1-deficient U251 glioma cells inhibits migration and invasion, reduces extracellular metalloproteinase activity, and promotes astrocytic differentiation with upregulation of GFAP.","method":"Scratch assay, Transwell invasion assay, zymography for metalloproteinase activity, Western blot for GFAP","journal":"Acta Academiae Medicinae Sinicae","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with defined molecular readouts, single study","pmids":["20078932"],"is_preprint":false},{"year":2025,"finding":"Constitutive Necl1/CADM3 knockout in rats causes prefrontal cortex-specific noradrenergic dysfunction characterized by norepinephrine depletion, dendritic spine loss, and upregulation of adrenergic receptor α2A (Adra2a); PFC-targeted Necl1 reconstitution rescues depressive phenotypes and normalizes Adra2a expression, establishing Necl1 as a synaptic-noradrenergic integrator.","method":"Constitutive KO in rats and mice, behavioral assays, PFC-targeted viral reconstitution, adrenergic receptor antagonism (mirtazapine), norepinephrine measurement","journal":"Journal of affective disorders","confidence":"High","confidence_rationale":"Tier 2 — bidirectional manipulation (KO + reconstitution) with pharmacological rescue and defined molecular pathway, cross-species validation","pmids":["41308882"],"is_preprint":false}],"current_model":"CADM3 (Necl-1/SynCAM3) is a neural tissue-specific, Ca2+-independent immunoglobulin-like cell adhesion molecule that mediates both homophilic and heterophilic trans-cellular adhesion (with Necl-2, nectin-1, nectin-3, and critically with glial Cadm4) through its V-domain dimer interface (Phe82-dependent), couples intracellularly to MAGUK scaffold proteins (Dlg3, Pals2, CASK) via its cytoplasmic tail, acts as the dominant axonal ligand for Schwann cell Cadm4 to organize myelinated fiber domains (Caspr, Kv1 channels), negatively regulates PNS myelination by dampening axonal ErbB3/PI3K/Akt signaling, directs cone synapse formation in the retina, supports prefrontal noradrenergic homeostasis, and functions as a tumor suppressor in neural tissues through mechanisms involving histone deacetylation-dependent silencing regulated by Sp1/HDAC1/p300 complexes."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that CADM3 mediates Ca²⁺-independent homophilic and heterophilic adhesion and couples to MAGUK scaffolds resolved its basic molecular mode of action as a synaptic/junctional adhesion molecule.","evidence":"Cell-cell adhesion assays, co-immunoprecipitation, immunoelectron microscopy in transfected cells","pmids":["15741237"],"confidence":"High","gaps":["Relative affinities for different heterophilic partners not quantified","In vivo relevance of MAGUK interactions not tested"]},{"year":2006,"claim":"Solving the crystal structure of the V-domain dimer and identifying Phe82 as critical for adhesion defined the atomic basis of Cadm3 homophilic interaction.","evidence":"2.4 Å crystal structure, size-exclusion chromatography, cross-linking, site-directed mutagenesis","pmids":["16467305"],"confidence":"High","gaps":["Structure of heterophilic complexes (e.g., Cadm3–Cadm4) not determined","No in vivo mutagenesis to confirm Phe82 requirement"]},{"year":2008,"claim":"Demonstrating that CADM3 overexpression induces synapse formation between neurons and non-neuronal cells established it as a synaptogenic adhesion molecule.","evidence":"Overexpression in HEK293-neuron co-culture, synaptosome fractionation","pmids":["18686604"],"confidence":"Medium","gaps":["Loss-of-function synaptogenic phenotype not shown in this study","Specific synaptic partners and downstream signaling not identified"]},{"year":2009,"claim":"Showing that CADM3 re-expression suppresses glioma proliferation, migration, and invasion while its silencing is governed by Sp1/HDAC1 at the promoter established its tumor suppressor function and epigenetic regulation.","evidence":"Cell cycle analysis, nude mouse xenograft, ChIP, co-IP for Sp1/HDAC1/p300, zymography, invasion assays","pmids":["19062177","20078932"],"confidence":"High","gaps":["Mechanism linking Cadm3 adhesion to cell cycle arrest undefined","Whether HDAC-mediated silencing occurs in other neural tumor types not tested"]},{"year":2011,"claim":"In vitro binding assays in zebrafish demonstrated that Cadm3 preferentially binds Cadm4 heterophilically, identifying the key axon–glia adhesion partnership.","evidence":"In vitro binding assays with zebrafish Cadm proteins, immunohistochemistry","pmids":["21456004"],"confidence":"Medium","gaps":["Quantitative affinity measurements not reported","Binding studied in zebrafish orthologs—mammalian specificity assumed but not directly shown"]},{"year":2016,"claim":"Bidirectional manipulation of axonal Cadm3 revealed that it negatively regulates PNS myelination by selectively dampening ErbB3/PI3K/Akt signaling, resolving how Cadm3 tunes myelin formation.","evidence":"shRNA knockdown and overexpression in DRG neuron–Schwann cell co-cultures, phospho-Western blots for ErbB3, Akt, Erk1/2","pmids":["27658374"],"confidence":"High","gaps":["Mechanism by which Cadm3 extracellular domain interferes with ErbB3 activation unresolved","In vivo confirmation of signaling effects not provided in this study"]},{"year":2021,"claim":"Genetic epistasis in triple-KO mice proved that Cadm3 is the dominant axonal ligand for glial Cadm4 in organizing myelinated fiber domains (Caspr, Kv1 channels), while the Tyr172Cys disease variant demonstrated that reduced surface expression and impaired Cadm4 interaction cause axonal CMT neuropathy.","evidence":"Single/double/triple Cadm1/2/3 KO mice, Cadm3-Y170C knock-in mice, STORM imaging, mass spectrometry, electrodiagnostics","pmids":["33397712","33889941"],"confidence":"High","gaps":["Whether Cadm3 signaling function (ErbB3 regulation) contributes to CMT pathology not tested","Structural basis of Cadm3–Cadm4 trans interaction not resolved at atomic level"]},{"year":2022,"claim":"SynCAM3 deletion reduced glial scar formation after spinal cord injury by preventing reactive-to-scar astrocyte transformation, revealing a CNS injury role for Cadm3.","evidence":"Cadm3 KO mice, spinal cord compression injury, scRNA-seq, behavioral assessment","pmids":["35682897"],"confidence":"Medium","gaps":["Mechanism by which Cadm3 promotes scar astrocyte transformation unknown","Not independently replicated"]},{"year":2023,"claim":"A second CADM3 missense variant (Gly368Cys) causing autosomal dominant axonal CMT confirmed CADM3 as a bona fide CMT disease gene and extended the loss-of-surface-expression pathomechanism.","evidence":"Whole exome sequencing, membrane protein level quantification by Western blot, structural prediction","pmids":["38074074"],"confidence":"Medium","gaps":["No knock-in animal model for this variant","Limited to structural prediction without experimental structural data"]},{"year":2024,"claim":"Cadm3 KO mice showed dislocated cone–OFF bipolar cell synapses and impaired short-wavelength cone signal transmission rescued by AMPA receptor potentiation, establishing Cadm3 as a retinal synapse organizer.","evidence":"Cadm3 KO mice, immunofluorescence, electroretinography, optokinetic response, pharmacological rescue","pmids":["38623325"],"confidence":"High","gaps":["Whether Cadm3 acts through Cadm4 or a different partner in retina not determined","Mechanism linking Cadm3 loss to AMPA receptor dislocation unresolved"]},{"year":2025,"claim":"Cadm3 KO in rats causes prefrontal norepinephrine depletion, spine loss, and Adra2a upregulation rescued by PFC-targeted reconstitution, establishing Cadm3 as a synaptic–noradrenergic integrator in prefrontal circuits.","evidence":"Constitutive KO rats and mice, PFC-targeted viral rescue, mirtazapine pharmacology, NE measurement, behavioral assays","pmids":["41308882"],"confidence":"High","gaps":["Direct molecular link between Cadm3 adhesion and noradrenergic terminal maintenance unknown","Whether this reflects a developmental or maintenance role not distinguished"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of the Cadm3–Cadm4 heterophilic complex, the mechanism by which the Cadm3 ectodomain dampens ErbB3 activation, and whether its synaptic, myelination-regulatory, and tumor-suppressive functions share common intracellular signaling intermediates.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of Cadm3–Cadm4 complex","Intracellular signaling downstream of Cadm3 adhesion poorly characterized beyond ErbB3/PI3K","Relationship between MAGUK scaffold recruitment and functional outcomes untested in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,4,6,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,7,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,6,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,10,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,10]}],"complexes":[],"partners":["CADM4","CADM1","CADM2","NECTIN1","NECTIN3","DLG3","CASK","MPP6"],"other_free_text":[]},"mechanistic_narrative":"CADM3 (Necl-1/SynCAM3) is a neural tissue-specific, calcium-independent immunoglobulin superfamily cell adhesion molecule that mediates homophilic and heterophilic trans-cellular adhesion—principally with Cadm4 at axon–glia interfaces—and organizes synaptic and myelinated fiber domains in both the central and peripheral nervous systems. Its N-terminal V-type Ig domain dimerizes through a Phe82-dependent interface to drive cell–cell adhesion, while its cytoplasmic tail recruits MAGUK scaffolds (Dlg3, Pals2, CASK) [PMID:15741237, PMID:16467305]. On myelinated axons, Cadm3 is the dominant ligand for Schwann cell Cadm4, organizing Caspr and Kv1 channel distribution and negatively regulating myelination by dampening ErbB3/PI3K/Akt signaling; loss-of-function variants (Tyr172Cys, Gly368Cys) that reduce surface expression cause axonal Charcot–Marie–Tooth neuropathy [PMID:33397712, PMID:27658374, PMID:33889941, PMID:38074074]. Cadm3 also directs cone-to-OFF bipolar cell synapse formation in the retina, maintains prefrontal noradrenergic homeostasis, promotes synaptogenesis, and acts as a tumor suppressor in glioma whose silencing is regulated by Sp1/HDAC1-dependent histone deacetylation [PMID:38623325, PMID:41308882, PMID:18686604, PMID:19062177]."},"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 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bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/17586627","citation_count":35,"is_preprint":false},{"pmid":"33397712","id":"PMC_33397712","title":"Differential Contribution of Cadm1-Cadm3 Cell Adhesion Molecules to Peripheral Myelinated Axons.","date":"2021","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33397712","citation_count":25,"is_preprint":false},{"pmid":"21456004","id":"PMC_21456004","title":"Localization of Cadm2a and Cadm3 proteins during development of the zebrafish nervous system.","date":"2011","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21456004","citation_count":23,"is_preprint":false},{"pmid":"29472641","id":"PMC_29472641","title":"BigR is a sulfide sensor that regulates a sulfur transferase/dioxygenase required for aerobic respiration of plant bacteria under sulfide stress.","date":"2018","source":"Scientific 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Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/17620720","citation_count":9,"is_preprint":false},{"pmid":"36959746","id":"PMC_36959746","title":"GRIK5 stimulates colon cancer growth and metastasis through cAMP/PKA/CADM3 signaling.","date":"2023","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/36959746","citation_count":8,"is_preprint":false},{"pmid":"36502948","id":"PMC_36502948","title":"Circ004463 promotes fibroblast proliferation and collagen I synthesis by sponging miR-23b and regulating CADM3/MAP4K4 via activation of AKT/ERK pathways.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36502948","citation_count":8,"is_preprint":false},{"pmid":"36344703","id":"PMC_36344703","title":"Usefulness of SynCAM3 and cyclin D1 immunohistochemistry in distinguishing superficial CD34-positive fibroblastic tumor from its histological mimics.","date":"2022","source":"Medical molecular morphology","url":"https://pubmed.ncbi.nlm.nih.gov/36344703","citation_count":6,"is_preprint":false},{"pmid":"38074074","id":"PMC_38074074","title":"Novel variant in CADM3 causes Charcot-Marie-Tooth disease.","date":"2023","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/38074074","citation_count":3,"is_preprint":false},{"pmid":"38623325","id":"PMC_38623325","title":"Necl-1/CADM3 regulates cone synapse formation in the mouse retina.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38623325","citation_count":2,"is_preprint":false},{"pmid":"38515057","id":"PMC_38515057","title":"Clinical significance of low expression of CADM3 in breast cancer and preliminary exploration of related mechanisms.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38515057","citation_count":2,"is_preprint":false},{"pmid":"20078932","id":"PMC_20078932","title":"[Neural adhesion molecule NECL1 inhibits migration, invasion, and potentially induces differentiation of glioma cell].","date":"2009","source":"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae","url":"https://pubmed.ncbi.nlm.nih.gov/20078932","citation_count":1,"is_preprint":false},{"pmid":"18686604","id":"PMC_18686604","title":"[Role of cell adhesion molecules Necl1 in synaptogenesis in primary cultured rat neurons].","date":"2008","source":"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae","url":"https://pubmed.ncbi.nlm.nih.gov/18686604","citation_count":1,"is_preprint":false},{"pmid":"18686605","id":"PMC_18686605","title":"[Effect of NECL1 on the proliferation of T98G glioma cell line].","date":"2008","source":"Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae","url":"https://pubmed.ncbi.nlm.nih.gov/18686605","citation_count":1,"is_preprint":false},{"pmid":"41308882","id":"PMC_41308882","title":"Necl1 deficiency induces noradrenergic dysfunction and depressive-like states in rodents: A cross-species model validated by pharmacological intervention.","date":"2025","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/41308882","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.22.666220","title":"Single-cell-based evidence for GLS1 inhibitor as a bona fide senolytic agent in vivo","date":"2025-07-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.22.666220","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.17.676751","title":"Placental transcriptome profiling in congenital Chagas disease: gene networks associated with transmission","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.676751","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.07.25329125","title":"Genetically determined ancestry associates with morphological and molecular carotid plaque features","date":"2025-06-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.07.25329125","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16995,"output_tokens":3520,"usd":0.051893},"stage2":{"model":"claude-opus-4-6","input_tokens":6905,"output_tokens":2891,"usd":0.1602},"total_usd":0.212093,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Necl-1/CADM3 exhibits Ca2+-independent homophilic cell-cell adhesion activity and heterophilic adhesion with Necl-2/SynCAM1, nectin-1 and nectin-3. Its C-terminal cytoplasmic region binds membrane-associated guanylate kinase (MAGUK) subfamily members containing the L27 domain, including Dlg3, Pals2 and CASK, but does not bind afadin.\",\n      \"method\": \"Cell-cell adhesion assays, co-immunoprecipitation, immunofluorescence and immunoelectron microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (adhesion assays, co-IP, immunoEM) in a single foundational study with 110 citations\",\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, crystallizes as a dimer confirmed by size-exclusion chromatography and chemical cross-linking, and Phe82 is a key residue for adhesion activity.\",\n      \"method\": \"Crystal structure at 2.4 Å, size-exclusion chromatography, chemical cross-linking, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and biochemical validation\",\n      \"pmids\": [\"16467305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Re-expression of NECL1/CADM3 in glioma cells represses proliferation by inducing cell cycle arrest and reduces tumor growth in vivo; loss of NECL1 expression in glioma is caused at least partly by histone deacetylation, mediated through Sp1 binding to either HDAC1 (in untreated cells) or p300/CBP (after TSA treatment) at the NECL1 promoter.\",\n      \"method\": \"Cell proliferation assays, flow cytometry, nude mouse xenograft, luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, HDAC activity assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, co-IP, luciferase reporter, in vivo xenograft) in a single study\",\n      \"pmids\": [\"19062177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Necl1/CADM3 expressed on Schwann cells (detected via Necl1-Fc affinity reagent) allows FACS-based isolation of myelination-competent Schwann cells, demonstrating that Necl1 is a surface marker mediating axon-Schwann cell contact.\",\n      \"method\": \"FACS-based cell isolation using Necl1-Fc fusion protein, myelinating co-culture assay\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional demonstration of Necl1 surface localization on Schwann cells with functional myelination readout, single study\",\n      \"pmids\": [\"19125407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In vitro binding assays with zebrafish cadm3 show that cadm3 binds heterophilically and preferentially to cadm4 (the glial partner), consistent with its role in axon-glia contact; cadm3 and cadm2a show largely non-overlapping expression in developing retina and spinal cord.\",\n      \"method\": \"In vitro binding assays, subtype-specific antibodies, immunohistochemistry\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro binding assay with single study; ortholog in zebrafish\",\n      \"pmids\": [\"21456004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Axonal Cadm3 negatively regulates Schwann cell myelination: shRNA knockdown of Cadm3 in DRG neurons promotes myelination, while overexpression almost completely prevents myelin segment formation. Cadm3 extracellular domain interferes dose-dependently with activation of ErbB3 and the pro-myelinating PI3K/Akt pathway but not the Mek/Erk1/2 pathway.\",\n      \"method\": \"shRNA knockdown, overexpression in DRG neuron/Schwann cell myelinating co-culture, Western blot for ErbB3/PI3K/Akt/Erk phosphorylation\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation (KD and OE) with defined pathway readout and selective signaling dissection\",\n      \"pmids\": [\"27658374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic epistasis in mice shows that Cadm3 is the main axonal ligand for glial Cadm4: triple knockout of Cadm1/2/3 phenocopies Cadm4 null abnormalities (Caspr and Kv1 potassium channel distribution defects); Cadm3 single KO combined with heterozygosity at Cadm1 and Cadm2 also produces defects, establishing a hierarchical adhesion code with Cadm3 as the dominant partner.\",\n      \"method\": \"Genetic epistasis (single, double, and triple knockout mice), immunofluorescence for Caspr and Kv1.2 distribution\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous genetic epistasis with multiple allele combinations, replicated phenotype across genotypes\",\n      \"pmids\": [\"33397712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A CADM3 Tyr172Cys variant causes axonal Charcot-Marie-Tooth disease; the mutation creates a novel disulfide bond altering protein conformation, causes ER retention and reduced cell surface expression, decreases co-localization with CADM4 at intercellular contact sites, and in Cadm3Y170C knock-in mice produces abnormal Kv1.2 channel and Caspr distribution without affecting myelin morphology.\",\n      \"method\": \"High-resolution mass spectrometry, STORM super-resolution microscopy, cell surface expression assay, Cadm3Y170C knock-in mice, immunofluorescence\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (MS, super-resolution imaging, knock-in mouse model) in a single rigorous study\",\n      \"pmids\": [\"33889941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SynCAM3/CADM3 deletion in mice reduces glial scar formation after spinal cord injury by preventing transformation of reactive astrocytes into scar-forming astrocytes, resulting in improved functional recovery and ECM reconstitution.\",\n      \"method\": \"SynCAM3 knockout mice, spinal cord compression injury, single-cell RNA sequencing, qRT-PCR, immunohistochemistry, behavioral assessment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype and functional readout, single study with multiple methods\",\n      \"pmids\": [\"35682897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A novel CADM3 Gly368Cys variant causes axonal CMT neuropathy with autosomal dominant inheritance; functional analysis shows significantly decreased mutant CADM3 protein levels at the membrane and major predicted structural changes, extending the disease mechanism established for the Tyr172Cys variant.\",\n      \"method\": \"Whole exome sequencing, Western blot for membrane protein levels, structural prediction analysis\",\n      \"journal\": \"Brain communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — cell surface expression assay plus structural prediction; single study, limited experimental methods\",\n      \"pmids\": [\"38074074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Necl-1/CADM3 localizes at S- and S/M-opsin-containing cones and dendrites of type 4 OFF cone bipolar cells; Necl-1 knockout mice exhibit dislocated cone-to-type 4 OFF CBC synapses, abnormal horizontal cell distribution, dislocated AMPA receptors, and impaired short-wavelength cone signal transmission rescued by an AMPA receptor potentiator, indicating Necl-1 regulates cone synapse formation for OFF pathways.\",\n      \"method\": \"Immunofluorescence localization, Necl-1 knockout mice, electroretinography, optokinetic response assay, pharmacological rescue with AMPA receptor potentiator\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal functional readouts and pharmacological rescue validation\",\n      \"pmids\": [\"38623325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Overexpression of Necl1/CADM3 in HEK293 cells induces synapse formation between cocultured 293 cells and neurons, and ectopic expression in primary neurons increases synapse density; Necl1 expression increases during neuronal differentiation and is found in synaptosome fractions.\",\n      \"method\": \"Overexpression in 293/primary neuron co-culture, immunofluorescence, synaptosome fractionation, Western blot\",\n      \"journal\": \"Zhongguo yi xue ke xue yuan xue bao\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional overexpression assay with synaptogenic readout plus subcellular fractionation, single study\",\n      \"pmids\": [\"18686604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Restoration of NECL1/CADM3 in NECL1-deficient U251 glioma cells inhibits migration and invasion, reduces extracellular metalloproteinase activity, and promotes astrocytic differentiation with upregulation of GFAP.\",\n      \"method\": \"Scratch assay, Transwell invasion assay, zymography for metalloproteinase activity, Western blot for GFAP\",\n      \"journal\": \"Acta Academiae Medicinae Sinicae\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with defined molecular readouts, single study\",\n      \"pmids\": [\"20078932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Constitutive Necl1/CADM3 knockout in rats causes prefrontal cortex-specific noradrenergic dysfunction characterized by norepinephrine depletion, dendritic spine loss, and upregulation of adrenergic receptor α2A (Adra2a); PFC-targeted Necl1 reconstitution rescues depressive phenotypes and normalizes Adra2a expression, establishing Necl1 as a synaptic-noradrenergic integrator.\",\n      \"method\": \"Constitutive KO in rats and mice, behavioral assays, PFC-targeted viral reconstitution, adrenergic receptor antagonism (mirtazapine), norepinephrine measurement\",\n      \"journal\": \"Journal of affective disorders\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (KO + reconstitution) with pharmacological rescue and defined molecular pathway, cross-species validation\",\n      \"pmids\": [\"41308882\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CADM3 (Necl-1/SynCAM3) is a neural tissue-specific, Ca2+-independent immunoglobulin-like cell adhesion molecule that mediates both homophilic and heterophilic trans-cellular adhesion (with Necl-2, nectin-1, nectin-3, and critically with glial Cadm4) through its V-domain dimer interface (Phe82-dependent), couples intracellularly to MAGUK scaffold proteins (Dlg3, Pals2, CASK) via its cytoplasmic tail, acts as the dominant axonal ligand for Schwann cell Cadm4 to organize myelinated fiber domains (Caspr, Kv1 channels), negatively regulates PNS myelination by dampening axonal ErbB3/PI3K/Akt signaling, directs cone synapse formation in the retina, supports prefrontal noradrenergic homeostasis, and functions as a tumor suppressor in neural tissues through mechanisms involving histone deacetylation-dependent silencing regulated by Sp1/HDAC1/p300 complexes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CADM3 (Necl-1/SynCAM3) is a neural tissue-specific, calcium-independent immunoglobulin superfamily cell adhesion molecule that mediates homophilic and heterophilic trans-cellular adhesion—principally with Cadm4 at axon–glia interfaces—and organizes synaptic and myelinated fiber domains in both the central and peripheral nervous systems. Its N-terminal V-type Ig domain dimerizes through a Phe82-dependent interface to drive cell–cell adhesion, while its cytoplasmic tail recruits MAGUK scaffolds (Dlg3, Pals2, CASK) [PMID:15741237, PMID:16467305]. On myelinated axons, Cadm3 is the dominant ligand for Schwann cell Cadm4, organizing Caspr and Kv1 channel distribution and negatively regulating myelination by dampening ErbB3/PI3K/Akt signaling; loss-of-function variants (Tyr172Cys, Gly368Cys) that reduce surface expression cause axonal Charcot–Marie–Tooth neuropathy [PMID:33397712, PMID:27658374, PMID:33889941, PMID:38074074]. Cadm3 also directs cone-to-OFF bipolar cell synapse formation in the retina, maintains prefrontal noradrenergic homeostasis, promotes synaptogenesis, and acts as a tumor suppressor in glioma whose silencing is regulated by Sp1/HDAC1-dependent histone deacetylation [PMID:38623325, PMID:41308882, PMID:18686604, PMID:19062177].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that CADM3 mediates Ca²⁺-independent homophilic and heterophilic adhesion and couples to MAGUK scaffolds resolved its basic molecular mode of action as a synaptic/junctional adhesion molecule.\",\n      \"evidence\": \"Cell-cell adhesion assays, co-immunoprecipitation, immunoelectron microscopy in transfected cells\",\n      \"pmids\": [\"15741237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative affinities for different heterophilic partners not quantified\", \"In vivo relevance of MAGUK interactions not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Solving the crystal structure of the V-domain dimer and identifying Phe82 as critical for adhesion defined the atomic basis of Cadm3 homophilic interaction.\",\n      \"evidence\": \"2.4 Å crystal structure, size-exclusion chromatography, cross-linking, site-directed mutagenesis\",\n      \"pmids\": [\"16467305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of heterophilic complexes (e.g., Cadm3–Cadm4) not determined\", \"No in vivo mutagenesis to confirm Phe82 requirement\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that CADM3 overexpression induces synapse formation between neurons and non-neuronal cells established it as a synaptogenic adhesion molecule.\",\n      \"evidence\": \"Overexpression in HEK293-neuron co-culture, synaptosome fractionation\",\n      \"pmids\": [\"18686604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Loss-of-function synaptogenic phenotype not shown in this study\", \"Specific synaptic partners and downstream signaling not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that CADM3 re-expression suppresses glioma proliferation, migration, and invasion while its silencing is governed by Sp1/HDAC1 at the promoter established its tumor suppressor function and epigenetic regulation.\",\n      \"evidence\": \"Cell cycle analysis, nude mouse xenograft, ChIP, co-IP for Sp1/HDAC1/p300, zymography, invasion assays\",\n      \"pmids\": [\"19062177\", \"20078932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking Cadm3 adhesion to cell cycle arrest undefined\", \"Whether HDAC-mediated silencing occurs in other neural tumor types not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vitro binding assays in zebrafish demonstrated that Cadm3 preferentially binds Cadm4 heterophilically, identifying the key axon–glia adhesion partnership.\",\n      \"evidence\": \"In vitro binding assays with zebrafish Cadm proteins, immunohistochemistry\",\n      \"pmids\": [\"21456004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative affinity measurements not reported\", \"Binding studied in zebrafish orthologs—mammalian specificity assumed but not directly shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Bidirectional manipulation of axonal Cadm3 revealed that it negatively regulates PNS myelination by selectively dampening ErbB3/PI3K/Akt signaling, resolving how Cadm3 tunes myelin formation.\",\n      \"evidence\": \"shRNA knockdown and overexpression in DRG neuron–Schwann cell co-cultures, phospho-Western blots for ErbB3, Akt, Erk1/2\",\n      \"pmids\": [\"27658374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Cadm3 extracellular domain interferes with ErbB3 activation unresolved\", \"In vivo confirmation of signaling effects not provided in this study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic epistasis in triple-KO mice proved that Cadm3 is the dominant axonal ligand for glial Cadm4 in organizing myelinated fiber domains (Caspr, Kv1 channels), while the Tyr172Cys disease variant demonstrated that reduced surface expression and impaired Cadm4 interaction cause axonal CMT neuropathy.\",\n      \"evidence\": \"Single/double/triple Cadm1/2/3 KO mice, Cadm3-Y170C knock-in mice, STORM imaging, mass spectrometry, electrodiagnostics\",\n      \"pmids\": [\"33397712\", \"33889941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cadm3 signaling function (ErbB3 regulation) contributes to CMT pathology not tested\", \"Structural basis of Cadm3–Cadm4 trans interaction not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SynCAM3 deletion reduced glial scar formation after spinal cord injury by preventing reactive-to-scar astrocyte transformation, revealing a CNS injury role for Cadm3.\",\n      \"evidence\": \"Cadm3 KO mice, spinal cord compression injury, scRNA-seq, behavioral assessment\",\n      \"pmids\": [\"35682897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Cadm3 promotes scar astrocyte transformation unknown\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A second CADM3 missense variant (Gly368Cys) causing autosomal dominant axonal CMT confirmed CADM3 as a bona fide CMT disease gene and extended the loss-of-surface-expression pathomechanism.\",\n      \"evidence\": \"Whole exome sequencing, membrane protein level quantification by Western blot, structural prediction\",\n      \"pmids\": [\"38074074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No knock-in animal model for this variant\", \"Limited to structural prediction without experimental structural data\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cadm3 KO mice showed dislocated cone–OFF bipolar cell synapses and impaired short-wavelength cone signal transmission rescued by AMPA receptor potentiation, establishing Cadm3 as a retinal synapse organizer.\",\n      \"evidence\": \"Cadm3 KO mice, immunofluorescence, electroretinography, optokinetic response, pharmacological rescue\",\n      \"pmids\": [\"38623325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cadm3 acts through Cadm4 or a different partner in retina not determined\", \"Mechanism linking Cadm3 loss to AMPA receptor dislocation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cadm3 KO in rats causes prefrontal norepinephrine depletion, spine loss, and Adra2a upregulation rescued by PFC-targeted reconstitution, establishing Cadm3 as a synaptic–noradrenergic integrator in prefrontal circuits.\",\n      \"evidence\": \"Constitutive KO rats and mice, PFC-targeted viral rescue, mirtazapine pharmacology, NE measurement, behavioral assays\",\n      \"pmids\": [\"41308882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between Cadm3 adhesion and noradrenergic terminal maintenance unknown\", \"Whether this reflects a developmental or maintenance role not distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of the Cadm3–Cadm4 heterophilic complex, the mechanism by which the Cadm3 ectodomain dampens ErbB3 activation, and whether its synaptic, myelination-regulatory, and tumor-suppressive functions share common intracellular signaling intermediates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of Cadm3–Cadm4 complex\", \"Intracellular signaling downstream of Cadm3 adhesion poorly characterized beyond ErbB3/PI3K\", \"Relationship between MAGUK scaffold recruitment and functional outcomes untested in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 4, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 7, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 6, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 10, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CADM4\",\n      \"CADM1\",\n      \"CADM2\",\n      \"NECTIN1\",\n      \"NECTIN3\",\n      \"DLG3\",\n      \"CASK\",\n      \"MPP6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}