{"gene":"NRCAM","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1991,"finding":"NrCAM (Nr-CAM) was identified as a new nervous system glycoprotein with a domain structure comprising six Ig-like domains, five fibronectin type III repeats, a transmembrane domain, and a short cytoplasmic domain, encoded by a single gene subject to alternative splicing yielding multiple isoforms.","method":"cDNA cloning, protein purification, SDS-PAGE, Northern/Southern blotting, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — full-length cDNA sequencing plus protein purification and N-terminal sequence confirmation in a single foundational study","pmids":["2045418"],"is_preprint":false},{"year":1992,"finding":"NrCAM mediates two distinct modes of cell adhesion: a homophilic, divalent cation-independent binding between neurons, and a heterophilic, divalent cation-dependent binding between neurons and other cell types (e.g., fibroblasts). The homophilic binding activity maps to the Ig domains and first FNIII repeat of the extracellular region.","method":"L-cell transfection aggregation assays, recombinant GST-Ig domain fusion protein (FGTNr) binding to cells and Covaspheres, antibody blocking","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with purified domains, multiple orthogonal binding assays, and functional blocking in a single rigorous study","pmids":["1527169"],"is_preprint":false},{"year":1992,"finding":"NrCAM/Bravo is a heterodimer composed of an α chain (~140/130 kD) and a β chain (60–80 kD) generated by proteolytic cleavage of an intact polypeptide at conserved Ser-Arg/Lys-Arg sites, analogous to L1 and Ng-CAM cleavage.","method":"cDNA cloning, protein biochemistry, SDS-PAGE of purified protein","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — direct protein biochemistry confirming heterodimer structure with sequence-level identification of cleavage site","pmids":["1512296"],"is_preprint":false},{"year":1993,"finding":"NrCAM/Bravo on axonal surfaces acts as a receptor for heterophilic binding to F11 (contactin family), and this interaction mediates neurite outgrowth of tectal cells. The binding site on F11 maps to the second or third Ig-like domain.","method":"Neurite outgrowth assays, antibody-blocking experiments, COS cell expression of F11 deletion mutants, cell binding assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1/2 — neurite outgrowth assay combined with domain-deletion mapping and antibody blocking, replicated in binding assays","pmids":["8274278"],"is_preprint":false},{"year":1994,"finding":"The cytoplasmic domains of NrCAM (and neurofascin, L1, NgCAM, neuroglian) directly associate with ankyrins (spectrin-binding proteins), providing a membrane-cytoskeletal linkage. NrCAM and neurofascin together constitute >0.5% of membrane protein in adult brain.","method":"In vitro biochemical binding assays between purified cytoplasmic domain constructs and ankyrin, protein quantification from brain membrane fractions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical reconstitution of ankyrin binding with purified cytoplasmic domain proteins","pmids":["7961622"],"is_preprint":false},{"year":1995,"finding":"In vivo, axonin-1 on commissural growth cones interacts with NrCAM on floor plate cells to guide commissural axons across the spinal cord midline; perturbation of either interaction causes commissural axons to fail to cross the midline and turn along the ipsilateral floor plate border.","method":"In vivo antibody perturbation in chick embryo spinal cord, immunohistochemistry","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — in vivo perturbation with specific antibodies producing defined guidance phenotype, highly cited foundational study","pmids":["7541632"],"is_preprint":false},{"year":1995,"finding":"NrCAM on peripheral glial cells serves as a receptor for axonin-1 on neurites, and this heterophilic interaction mediates neurite–glial cell contact formation during the early phase of axon ensheathment in dorsal root ganglia.","method":"Fluorescent microsphere binding assays with purified axonin-1 and NrCAM, antibody blocking of neurite–glia contact in DRG cultures","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — purified protein binding plus functional cell culture perturbation assays with specific antibodies","pmids":["7490283"],"is_preprint":false},{"year":1996,"finding":"NrCAM and neurofascin (NF) interact heterophilically through their Ig domains; immobilized neurofascin induces neurite outgrowth of tectal cells via NrCAM on the axonal surface, while immobilized NrCAM induces neurite outgrowth via F11 (not neurofascin) as the axonal receptor. This heterophilic binding can be modulated by alternative splicing within neurofascin.","method":"Neurite outgrowth assays on immobilized substrates, antibody blocking, COS7 cell transfection binding assays, immunoprecipitation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — reciprocal substrate assays, direct binding by immunoprecipitation, and receptor identification by antibody blocking in a single study","pmids":["8922386"],"is_preprint":false},{"year":1996,"finding":"NrCAM is concentrated at the node of Ranvier and at axon initial segments, co-localizing with ankyrinG and voltage-dependent sodium channels in myelinated axons. This is the first identification of defined neuronal CAMs at nodal axon segments.","method":"Immunofluorescence localization with isoform-specific antibodies; library screen identifying rat NrCAM; co-localization with ankyrinG and Na+ channels","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization with functional context (nodal Na+ channel clustering), widely replicated","pmids":["8947556"],"is_preprint":false},{"year":1997,"finding":"NrCAM and contactin form a cis complex on the neuronal surface that serves as a receptor for glial RPTPβ; binding of RPTPβ to this complex (through its carbonic anhydrase domain) promotes neurite outgrowth and neuronal differentiation.","method":"Neurite outgrowth assays, antibody blocking, co-immunoprecipitation of contactin/NrCAM complex with RPTPβ-Fc fusion proteins, NIH-3T3 surface expression of RPTPβ","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — co-IP of complex, antibody blocking of outgrowth, and cell surface expression system in a single rigorous study","pmids":["9049255"],"is_preprint":false},{"year":1999,"finding":"NrCAM serves as a ligand that promotes neurite outgrowth from peripheral (DRG and sympathetic) but not central neurons, and axonin-1 functions as the neuronal receptor for NrCAM in this context; antibodies to axonin-1 block NrCAM-Fc-induced outgrowth.","method":"NrCAM-Fc substrate neurite outgrowth assays with DRG, sympathetic, tectal, and forebrain neurons; antibody blocking; in ovo injection of NrCAM-Fc causing commissural axon guidance errors","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — multiple neuron types compared, antibody blocking identifies receptor, in vivo injection validates guidance role","pmids":["10328925"],"is_preprint":false},{"year":1999,"finding":"NrCAM acts as a receptor for F3/contactin on cerebellar granule cells; F3Fc-coated microspheres bind to growth cones via NrCAM (not L1), and their retrograde movement at the growth cone is coupled to actin filament retrograde flow—disruption by cytochalasin B abolishes movement.","method":"Microsphere binding assays with antibody blocking, time-lapse video microscopy, cytochalasin B actin disruption","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — live imaging plus pharmacological actin disruption and receptor identification in a single mechanistic study","pmids":["10462518"],"is_preprint":false},{"year":2000,"finding":"Axonin-1 interaction with NrCAM at the floor plate mediates commissural axon guidance (turning) without promoting axon elongation; perturbation of NrCAM + NgCAM but not either alone is required for longitudinal post-crossing growth, indicating distinct guidance and growth signals.","method":"Stripe choice assays in vitro, antibody blocking, in vivo perturbation of commissural axon pathfinding in chick embryo","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — in vitro stripe assay, in vivo genetic epistasis-like perturbation, separating guidance from growth signals","pmids":["10811834"],"is_preprint":false},{"year":2001,"finding":"NrCAM null mice develop mature cataracts caused by disorganization of lens fibers accompanied by cytoskeletal abnormalities and disruption of connexin50-containing gap junctions; ankyrin-B null mice show an identical lens fiber disorganization, providing genetic evidence that NrCAM–ankyrin-B interaction is required to maintain lens fiber cell contact.","method":"NrCAM knockout mice, ankyrin-B mutant mice, histology, electron microscopy, immunostaining for connexin50 and cytoskeletal proteins","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — two independent mutant mouse lines show identical phenotype, establishing genetic interaction between NrCAM and ankyrin-B","pmids":["11449000"],"is_preprint":false},{"year":2001,"finding":"NrCAM and neurofascin function cooperatively at developing nodes of Ranvier: an NrCAM-Fc fusion protein specifically inhibits Na+ channel and ankyrinG accumulation at nodes in myelinating DRG–Schwann cell cocultures, and NrCAM-Fc clusters and co-precipitates neurofascin on axons, revealing that neurofascin plays a major role in node formation via interactions with NrCAM.","method":"Myelinating DRG–Schwann cell cocultures, NrCAM-Fc perturbation, immunofluorescence for Na+ channels and ankyrinG, co-immunoprecipitation of neurofascin by NrCAM-Fc","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — functional perturbation in culture plus co-IP demonstrating direct molecular interaction in a single study","pmids":["11728309"],"is_preprint":false},{"year":2001,"finding":"Nr-CAM-deficient cerebellar granule cells fail to extend neurites on contactin substrate in vitro, confirming contactin as an NrCAM ligand; mice doubly deficient for L1 and Nr-CAM exhibit severe cerebellar folial defects and reduced inner granule cell layer thickness not seen in either single mutant, indicating overlapping functions.","method":"NrCAM-null mouse neuronal culture, L1/NrCAM double-null mouse histology, antibody perturbation assays in cerebellar cultures","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via double knockout plus in vitro functional assay confirms ligand identity and functional redundancy","pmids":["11564762"],"is_preprint":false},{"year":2002,"finding":"NrCAM is a direct transcriptional target of the β-catenin/LEF-1 pathway; LEF/TCF binding sites in the NrCAM promoter are required for its activation by β-catenin or plakoglobin; retroviral transduction of NrCAM stimulates cell growth, motility, and transformation, and anti-NrCAM antibodies inhibit melanoma cell motility.","method":"DNA microarray, promoter-reporter assays with LEF/TCF site mutations, retroviral transduction, nude mouse tumor assays, antibody blocking of motility","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — promoter mutagenesis plus functional gain-of-function in vitro and in vivo, multiple orthogonal methods","pmids":["12183361"],"is_preprint":false},{"year":2003,"finding":"In the peripheral nervous system, NrCAM (ankyrinG-binding protein) accumulates at nascent node sites prior to Na+ channels; both Na+ channel and ankyrinG sequestration at developing nodes are delayed in NrCAM null mutants, and NrCAM action is local and linked to glial contact. Computational modeling supports lateral diffusion of Na+ channels with fast cytoskeletal anchoring by ankyrinG enabled by early NrCAM arrival.","method":"NrCAM null mouse PNS, immunofluorescence during remyelination, computational diffusion-clustering model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — null mouse phenotype with quantitative immunofluorescence during development plus modeling to test mechanism","pmids":["14602817"],"is_preprint":false},{"year":2004,"finding":"NrCAM coupling to the retrograde actin flow in neuroblastoma growth cones requires both the FNIII domains (for cis-interactions) and lipid raft partitioning, but not the cytoplasmic tail alone; TAG-1 bead binding induces coalescence of lipid rafts and recruitment of caveolin-1 at the adhesive contact.","method":"Optical tweezers, single particle tracking of TAG-1 beads on NrCAM deletion mutants, cholesterol depletion (methyl-β-cyclodextrin), FRAP, immunostaining for caveolin-1","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1/2 — biophysical single-particle tracking combined with pharmacological manipulation and FRAP in a rigorous mechanistic study","pmids":["15254265"],"is_preprint":false},{"year":2005,"finding":"NrCAM is shed from the cell surface by metalloprotease-mediated ectodomain cleavage; the shed ectodomain and conditioned medium activate ERK and AKT signaling and enhance cell motility and proliferation. NrCAM forms a complex with α4β1 integrins in melanoma cells, indicating heterophilic adhesion with extracellular matrix receptors contributes to its oncogenic function.","method":"Conditioned medium experiments, NrCAM-Fc fusion protein treatment, co-immunoprecipitation with integrins, siRNA knockdown of NrCAM, NIH3T3 transformation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — co-IP of integrin complex, metalloprotease shedding characterized, signaling pathway activation confirmed, functional rescue by secreted ectodomain","pmids":["16357171"],"is_preprint":false},{"year":2005,"finding":"NrCAM promotes retinal ganglion cell (RGC) axon extension and correct pathfinding toward the optic fissure in the developing retina; NrCAM inhibition in organ-cultured eyes causes RGC axons to misroute at the optic fissure toward the opposite retinal side rather than entering the optic nerve head.","method":"Immunostaining of chick retina, substrate assays, stripe preference assays, time-lapse imaging of growth cones, antibody-blocking organ culture","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays including time-lapse imaging and organ-culture perturbation with specific antibodies","pmids":["16033798"],"is_preprint":false},{"year":2006,"finding":"NrCAM expressed on contralaterally-projecting retinal ganglion cells is critical for guidance of late-born RGCs through the optic chiasm; blocking NrCAM function increases the ipsilateral projection and reduces neurite outgrowth on chiasm cells in an age- and region-specific manner. EphB1/ephrin-B2-mediated repulsion and NrCAM-mediated attraction represent distinct molecular programs for binocular visual pathway formation.","method":"NrCAM null mice, anterograde axon tracing, in vitro neurite outgrowth on chiasm cells with antibody blocking","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — null mouse in vivo tracing plus in vitro functional assay, identifying NrCAM-attraction as distinct from EphB-repulsion","pmids":["16701205"],"is_preprint":false},{"year":2006,"finding":"The cytoplasmic C-terminus of NrCAM contains a PDZ-binding motif that specifically interacts with class I PDZ domains of the scaffold proteins SAP90/PSD-95 and SAP97; this interaction recruits SAP97 to the plasma membrane and is distinct from L1, CHL1, and neurofascin.","method":"Pull-down assays with cytoplasmic domain constructs, co-transfection of COS-7 cells, co-localization in photoreceptor terminals","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — biochemical pull-down confirming direct PDZ interaction, functional recruitment assay in cells, and co-localization in tissue","pmids":["16882004"],"is_preprint":false},{"year":2010,"finding":"In the peripheral nervous system, glial NrCAM and gliomedin together act through axonal neurofascin 186 (NF186) to cluster Na+ channels at heminodes during early node of Ranvier formation; a second paranodal junction-dependent mechanism then concentrates Na+ channels at mature nodes by restricting their diffusion.","method":"NrCAM and gliomedin null mice, immunofluorescence during PNS myelination, electron microscopy","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — null mouse analysis during development, mechanistic dissection of two cooperative clustering mechanisms, highly cited","pmids":["20188654"],"is_preprint":false},{"year":2011,"finding":"NrCAM forms a molecular complex with neuropilin-2 (Npn-2) in brain and neurons, and is required for Sema3F-induced growth cone collapse in thalamic neurons; NrCAM deletion causes mistargeting of thalamocortical axons to visual cortex and disrupts visual acuity.","method":"NrCAM null mice, Npn-2 null mice, anterograde axon tracing, co-immunoprecipitation of NrCAM–Npn-2 complex, growth cone collapse assay in thalamic neuron cultures","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — co-IP of complex, null mouse phenotype with axon tracing, functional growth cone collapse assay, multiple orthogonal methods","pmids":["21273439"],"is_preprint":false},{"year":2012,"finding":"Sema6D and NrCAM are expressed on midline radial glia while Plexin-A1 and NrCAM are expressed on contralateral RGCs; NrCAM functions as a receptor for Sema6D, and a tripartite Sema6D/Nr-CAM/Plexin-A1 complex converts Sema6D repulsion to growth promotion, enabling RGC decussation at the optic chiasm.","method":"In situ hybridization and immunostaining of optic chiasm, RGC-specific perturbation, in vitro growth assays, receptor-ligand binding assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — receptor identification, complex characterization, in vitro and in vivo functional assays defining sign-conversion mechanism","pmids":["22632726"],"is_preprint":false},{"year":2013,"finding":"NrCAM contributes to mediolateral retinocollicular axon targeting; EphB2 tyrosine kinase phosphorylates NrCAM at a conserved tyrosine in the FIGQY ankyrin-binding motif, reducing ankyrin recruitment and modulating linkage of NrCAM to the actin cytoskeleton. Phospho-FIGQY levels of NrCAM in SC correlate with EphB activity in multiple mutant mouse backgrounds.","method":"EphB2 kinase phosphorylation assay, mutagenesis of FIGQY site, ankyrin recruitment in HEK293 cells, anterograde RGC axon tracing in NrCAM and EphB null mice, phospho-FIGQY immunostaining","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1/2 — kinase assay with mutagenesis, functional ankyrin recruitment assay, validated in multiple mouse mutant backgrounds","pmids":["24023801"],"is_preprint":false},{"year":2014,"finding":"NrCAM localizes to dendritic spines of cortical pyramidal neurons and forms a complex with Sema3F receptor subunits Neuropilin-2 (Npn-2) and PlexinA3 (PlexA3) through an Npn-2-binding sequence (TARNER) in its extracellular Ig1 domain; NrCAM deletion elevates spine densities and increases mEPSC frequency, and re-expression of NrCAM rescues Sema3F-induced spine retraction.","method":"NrCAM null mice, co-immunoprecipitation, electron microscopy, whole-cell patch-clamp recordings, rescue experiments with NrCAM re-expression, trans-heterozygous genetic interaction test","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1/2 — co-IP defining complex, electrophysiology, EM, rescue experiment, and genetic epistasis in a single comprehensive study","pmids":["25143608"],"is_preprint":false},{"year":2014,"finding":"Long-term maintenance of Na+ channels at nodes of Ranvier requires continued axon-glial contact mediated by both gliomedin and NrCAM together; mice lacking both molecules show gradual loss of Na+ channels, NF186, ankyrinG, and βIV spectrin from nodes in an ordered sequence mirroring assembly, formation of binary nodes, and Schwann cell invasion of the nodal gap.","method":"Gliomedin/NrCAM double null mice, immunofluorescence time-course, electrophysiology (nerve conduction), electron microscopy","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — double null mouse with detailed temporal immunofluorescence, electrophysiology, and EM revealing ordered disassembly mechanism","pmids":["24719088"],"is_preprint":false},{"year":2019,"finding":"NrCAM is a substrate of ADAM10; ADAM10 controls NrCAM surface levels and regulates neurite outgrowth in an NrCAM-dependent manner in vitro. Unlike APP, ADAM10 cleavage of NrCAM is not stimulated by the ADAM10 activator acitretin, demonstrating substrate-selective ADAM10 activation.","method":"ADAM10 activation/inhibition assays, NrCAM surface level measurement, neurite outgrowth assays, CSF proteomics from clinical trial samples","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — in vitro functional assay with ADAM10 manipulations, NrCAM-dependence confirmed, validated in human CSF proteomics","pmids":["30833305"],"is_preprint":false},{"year":2019,"finding":"NrCAM acts cell-autonomously in adolescent cortical pyramidal neurons to limit dendritic spine density; it promotes clustering of the Sema3F holoreceptor (Npn-2/PlexA3) by interfacing with Npn-2 and PDZ scaffold SAP102, thereby stimulating PlexA3 Rap-GAP activity, inhibiting Rap1-GTPase, and inactivating adhesive β1 integrins to drive Sema3F-induced spine pruning.","method":"Conditional inducible NrCAM knockout mice (Nex1Cre-ERT2:NrCAMflox/flox), molecular modeling, co-immunoprecipitation of holoreceptor complex, Rap1-GTPase and β1-integrin activity assays","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 — inducible cell-autonomous KO, biochemical signaling cascade delineated by co-IP and GTPase assays in a single study","pmids":["29415226"],"is_preprint":false},{"year":2018,"finding":"Neurocan (a chondroitin sulfate proteoglycan) inhibits Sema3F-induced spine elimination by physically associating with NrCAM; glycosaminoglycan chain interactions of neurocan are required for this inhibitory effect on the NrCAM/Npn-2/PlexA3 Sema3F holoreceptor complex.","method":"ELISA binding assays, COS-7 cell morphological retraction assay, antibody blocking, spine elimination assay in cortical neuron cultures, immunoelectron microscopy","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay, functional cell assay with domain-deletion analysis, EM localization","pmids":["30356641"],"is_preprint":false},{"year":2020,"finding":"Alternative splicing of Nrcam exon 10 in dorsal root ganglia contributes to neuropathic pain; spinal nerve ligation increases exon 10 insertion (Nrcam+10 isoform), and antisense oligonucleotides targeting exon 10 that shift splicing toward the Nrcam-10 isoform attenuate mechanical allodynia, thermal hyperalgesia, and cold allodynia in mice.","method":"RNA-seq, antisense oligonucleotide splicing manipulation, DRG microinjection, intrathecal injection, behavioral pain assays (von Frey, Hargreaves, acetone) in mice","journal":"The journal of pain","confidence":"High","confidence_rationale":"Tier 2 — RNA-seq identification, ASO-mediated isoform switching with in vivo behavioral rescue, validated in two pain models","pmids":["31917219"],"is_preprint":false},{"year":2025,"finding":"NrCAM and Ankyrin B mediate perisomatic synaptic contact between cholecystokinin (CCK) basket interneurons and pyramidal neurons in mouse medial prefrontal cortex; NrCAM null mice show a significant decrease in CCK-BC (but not PV-BC) synaptic puncta on PN soma, and Ankyrin B deletion from PNs phenocopies this loss.","method":"NrCAM null mice, Ankyrin B conditional knockout (Nex1Cre-ERT2:Ank2flox/flox), VGLUT3/VGAT immunolabeling, CCK-BC reporter mouse (Sncg-tdT), NrCAM co-localization with Sncg+ CCK-BCs","journal":"Current research in neurobiology","confidence":"High","confidence_rationale":"Tier 2 — two independent genetic deletions (NrCAM null and Ankyrin B conditional KO) converging on same synaptic phenotype, with reporter mouse for CCK-BC identification","pmids":["40276719"],"is_preprint":false},{"year":2025,"finding":"A tumor-specific NrCAM proteoform lacking microexons 5 and 19 (Δex5Δex19 NRCAM) is uniformly expressed in pediatric high-grade gliomas; this proteoform (but not full-length NrCAM) is essential for pHGG cell migration and invasion in vitro and tumor growth in vivo, and a monoclonal antibody selective for Δex5Δex19 NrCAM enables T-cell-mediated tumor killing.","method":"Bulk and single-nuclei RNA-seq (short- and long-read), in vitro migration/invasion assays, in vivo tumor growth assays, monoclonal antibody development, FcRI-based universal immune receptor T-cell killing assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1/2 — loss-of-function in vitro and in vivo, isoform-specific antibody, and T-cell killing assay in a single comprehensive study","pmids":["40782352"],"is_preprint":false},{"year":2023,"finding":"Rbfox1 (an RNA-binding protein) regulates alternative splicing of NrCAM exon 10 in dorsal root ganglia; peripheral nerve injury downregulates Rbfox1, increasing L-Nrcam (exon 10-included) variants; restoring Rbfox1 reduces nociceptive hypersensitivity, while mimicking its downregulation induces neuropathic pain.","method":"Transcriptome profiling of DRG after SNL, bioinformatics, lentiviral Rbfox1 overexpression and knockdown, RT-PCR isoform quantification, behavioral pain assays","journal":"Neurotherapeutics","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function of splicing regulator with direct measurement of NrCAM isoform ratios and behavioral validation","pmids":["38241164"],"is_preprint":false},{"year":2017,"finding":"NrCAM activates MAPK/ERK and PI3K/AKT signaling pathways in thyroid cancer via ectodomain shedding and binding to EGFR and α4β1 integrins; in turn, these pathways drive NrCAM overexpression through the GSK3β/β-catenin axis, forming a positive feedback loop.","method":"NrCAM knockdown/overexpression in thyroid cancer cells, co-immunoprecipitation with EGFR and integrins, in vivo nude mouse xenografts, BrafV600E transgenic mice","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP of receptor complexes plus in vivo validation, but signaling pathway attribution relies on standard inhibitor experiments in a single lab","pmids":["27732334"],"is_preprint":false},{"year":2023,"finding":"In hepatocellular carcinoma liver cancer stem cells, NrCAM activates EMT and metastasis-related MMPs through the MACF1-mediated β-catenin signaling pathway, facilitating intra-hepatic and lung metastasis.","method":"NrCAM inhibition in MYC-driven LCSC organoids, in vivo tumor allografts, scRNA-seq, co-immunoprecipitation/pathway analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro and in vivo evidence with mechanistic pathway (MACF1/β-catenin) identified, single lab study","pmids":["37993901"],"is_preprint":false},{"year":2021,"finding":"Alternative splicing of Nrcam exon 10 regulates neurite outgrowth of DRG neurons; antisense oligonucleotides targeting exon 10 (shifting toward short Nrcam variants) suppress neurite length in multiple DRG neuron subtypes via activation of EGFR signaling.","method":"DRG primary culture, Nrcam ASO treatment, immunostaining with DRG subtype markers, EGFR activation assays","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, ASO manipulation with immunostaining and signaling marker, no direct isoform rescue experiment","pmids":["33850082"],"is_preprint":false},{"year":2022,"finding":"NrCAM secreted by endometrial stromal cells increases progestin sensitivity of endometrial cancer cells by upregulating PRB through TET1-induced hydroxymethylation of the PRB gene promoter region.","method":"Co-culture experiments, NrCAM ELISA in conditioned medium, nude mouse xenografts with MPA±NrCAM, TET1 knockdown, bisulfite sequencing of PRB promoter hydroxymethylation","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 — direct mechanistic link (TET1-mediated PRB hydroxymethylation) plus in vivo validation, single lab","pmids":["35388173"],"is_preprint":false}],"current_model":"NrCAM is an L1-family Ig/FNIII cell adhesion molecule that mediates homophilic and heterophilic adhesion (with axonin-1/TAG-1, contactin/F3, neurofascin, Sema6D, gliomedin, RPTPβ, EGFR, and α4β1 integrins) and links extracellular signals to the actin cytoskeleton via its cytoplasmic domain interactions with ankyrin (G and B) and PDZ scaffold proteins (SAP90/PSD-95, SAP97); at the node of Ranvier, glial NrCAM and gliomedin cluster Na+ channels through axonal NF186 both during development and for long-term maintenance, while in cortical neurons NrCAM assembles the Sema3F holoreceptor complex (Npn-2/PlexA3/SAP102) to activate PlexA3 Rap-GAP activity and prune dendritic spines, and its ectodomain shedding by metalloproteases (including ADAM10) generates a soluble ligand that activates ERK/AKT signaling to promote cell motility and oncogenesis."},"narrative":{"teleology":[{"year":1991,"claim":"Identification of NrCAM as a new neural Ig/FNIII cell adhesion molecule with alternative splicing established a foundational structural framework for understanding L1-family adhesion in the nervous system.","evidence":"cDNA cloning, protein purification, SDS-PAGE, Northern/Southern blotting from chick brain","pmids":["2045418"],"confidence":"High","gaps":["Three-dimensional structure not determined","Functional significance of individual splice variants unknown"]},{"year":1992,"claim":"Demonstration that NrCAM mediates both homophilic (cation-independent) and heterophilic (cation-dependent) cell adhesion, with homophilic binding mapped to Ig domains and first FNIII repeat, established dual adhesion modalities and identified the first functional domains.","evidence":"L-cell transfection aggregation assays, recombinant GST-domain fusion binding, antibody blocking","pmids":["1527169","1512296"],"confidence":"High","gaps":["Identity of heterophilic ligands unknown","Structural basis of cation-dependent vs. cation-independent adhesion unresolved"]},{"year":1993,"claim":"Discovery that contactin-family F11 on neurons binds NrCAM heterophilically to promote neurite outgrowth identified the first trans-heterophilic partner and linked NrCAM to axon growth signaling.","evidence":"Neurite outgrowth assays, COS cell F11 deletion mutants, antibody blocking","pmids":["8274278"],"confidence":"High","gaps":["Signaling cascade downstream of NrCAM–F11 interaction undefined","Whether this is a general or context-specific interaction unknown"]},{"year":1994,"claim":"Biochemical demonstration that NrCAM's cytoplasmic domain directly binds ankyrins established the membrane-cytoskeleton linkage mechanism shared across the L1 family.","evidence":"In vitro binding assays between purified cytoplasmic domains and ankyrin","pmids":["7961622"],"confidence":"High","gaps":["Regulation of ankyrin binding (e.g., by phosphorylation) not yet addressed","Functional consequence of ankyrin association in vivo untested"]},{"year":1995,"claim":"In vivo antibody perturbation showed that axonin-1/NrCAM interaction at the floor plate is required for commissural axon midline crossing, providing the first in vivo guidance function for NrCAM.","evidence":"Anti-NrCAM and anti-axonin-1 antibody injection in chick embryo spinal cord with immunohistochemistry","pmids":["7541632","7490283"],"confidence":"High","gaps":["Intracellular signaling triggered by axonin-1–NrCAM binding at the floor plate not characterized","Redundancy with other L1-family members at midline untested"]},{"year":1996,"claim":"Localization of NrCAM to nodes of Ranvier with ankyrinG and Na⁺ channels, plus demonstration of reciprocal NrCAM–neurofascin heterophilic interactions modulated by splicing, established NrCAM as a key nodal organizer and defined a second major heterophilic partner.","evidence":"Immunofluorescence at nodes/axon initial segments; neurite outgrowth substrate assays and co-immunoprecipitation of neurofascin–NrCAM","pmids":["8947556","8922386"],"confidence":"High","gaps":["Whether NrCAM is required for Na⁺ channel clustering at nodes not yet tested genetically","Mechanism of NrCAM initial targeting to nodes unknown"]},{"year":1997,"claim":"Identification of a cis contactin/NrCAM complex as a neuronal receptor for glial RPTPβ linked NrCAM to receptor phosphatase signaling and demonstrated a tripartite signaling complex promoting neurite outgrowth.","evidence":"Co-immunoprecipitation of contactin/NrCAM with RPTPβ-Fc; antibody-blocking neurite outgrowth assays","pmids":["9049255"],"confidence":"High","gaps":["Phosphatase substrates downstream of RPTPβ at the NrCAM complex unknown","Stoichiometry of the tripartite complex unresolved"]},{"year":2001,"claim":"NrCAM knockout mice revealed a non-neural requirement: NrCAM–ankyrin-B interaction maintains lens fiber cell organization, with loss causing cataracts; separately, NrCAM-Fc perturbation and double-knockout with L1 demonstrated cooperative roles in node of Ranvier formation and cerebellar development.","evidence":"NrCAM null mice, ankyrin-B null mice, DRG–Schwann cell myelinating cocultures, L1/NrCAM double null histology","pmids":["11449000","11728309","11564762"],"confidence":"High","gaps":["Molecular basis of NrCAM–ankyrin-B specificity vs. ankyrin-G at nodes not resolved","Whether cataract phenotype reflects a broader non-neural adhesion role unknown"]},{"year":2002,"claim":"Identification of NrCAM as a direct β-catenin/LEF-1 transcriptional target whose overexpression drives cell motility, growth, and transformation established NrCAM as a Wnt pathway effector gene with oncogenic potential.","evidence":"Promoter-reporter assays with LEF/TCF site mutations, retroviral transduction, nude mouse tumor assays","pmids":["12183361"],"confidence":"High","gaps":["Physiological contexts where Wnt-driven NrCAM upregulation is relevant beyond melanoma not yet explored","Whether NrCAM oncogenic activity requires specific splice isoforms unknown"]},{"year":2003,"claim":"Analysis of NrCAM null mice during PNS development showed NrCAM arrives at nascent nodes before Na⁺ channels and is needed for efficient ankyrinG/Na⁺ channel clustering, establishing a temporal hierarchy in node assembly.","evidence":"NrCAM null mouse PNS immunofluorescence during remyelination, computational diffusion-clustering model","pmids":["14602817"],"confidence":"High","gaps":["NrCAM's role in CNS node formation less clear","Direct visualization of Na⁺ channel lateral diffusion trapping not achieved"]},{"year":2004,"claim":"Biophysical analysis revealed that NrCAM coupling to retrograde actin flow requires FNIII-mediated cis-interactions and lipid raft partitioning rather than the cytoplasmic tail alone, redefining the force-transmission mechanism.","evidence":"Optical tweezers and single-particle tracking of TAG-1 beads on NrCAM deletion mutants in neuroblastoma growth cones","pmids":["15254265"],"confidence":"High","gaps":["Identity of the cis-interacting partner in lipid rafts not fully resolved","Whether this mechanism operates at nodes of Ranvier untested"]},{"year":2005,"claim":"Discovery of metalloprotease-mediated NrCAM ectodomain shedding generating a soluble fragment that activates ERK/AKT and promotes motility, plus identification of α4β1 integrin as a co-receptor, revealed the signaling mechanism underlying NrCAM's oncogenic activity.","evidence":"NrCAM-Fc treatment, conditioned medium experiments, co-immunoprecipitation with integrins, siRNA knockdown, NIH3T3 transformation","pmids":["16357171"],"confidence":"High","gaps":["Identity of the metalloprotease responsible not determined at this stage","Structural basis of NrCAM–integrin interaction unresolved"]},{"year":2005,"claim":"Functional studies in retina showed NrCAM promotes RGC axon extension and correct pathfinding at the optic fissure, extending its guidance role to the visual system.","evidence":"Antibody-blocking organ culture of chick retina, time-lapse imaging, stripe preference assays","pmids":["16033798","16701205"],"confidence":"High","gaps":["Downstream signaling in RGC growth cones not defined","Relative contribution of NrCAM vs. other cues at the optic chiasm not quantified"]},{"year":2006,"claim":"Identification of NrCAM's C-terminal PDZ-binding motif interaction with SAP90/PSD-95 and SAP97 provided a scaffold-coupling mechanism distinct from the ankyrin linkage, expanding the repertoire of cytoplasmic signaling outputs.","evidence":"Pull-down assays with cytoplasmic domain constructs, COS-7 co-transfection, co-localization in photoreceptor terminals","pmids":["16882004"],"confidence":"High","gaps":["Functional consequence of NrCAM–PSD-95 interaction at synapses not established","Whether PDZ and ankyrin binding are mutually exclusive or cooperative unknown"]},{"year":2010,"claim":"Double-null mouse analysis established that glial NrCAM and gliomedin cooperate through axonal NF186 for initial Na⁺ channel clustering at heminodes, with a second paranodal mechanism acting at mature nodes, resolving the cooperative mechanism of node assembly.","evidence":"NrCAM and gliomedin null mice, developmental immunofluorescence in PNS, electron microscopy","pmids":["20188654"],"confidence":"High","gaps":["CNS node formation mechanism by NrCAM less defined","Whether NrCAM acts as a direct ligand for NF186 or only through gliomedin unclear"]},{"year":2012,"claim":"Discovery that NrCAM functions as a Sema6D receptor and forms a tripartite Sema6D/NrCAM/PlexA1 complex that converts repulsion to growth promotion at the optic chiasm revealed a novel sign-conversion mechanism in axon guidance.","evidence":"Receptor-ligand binding, in vitro growth assays, RGC-specific perturbation at the optic chiasm","pmids":["22632726"],"confidence":"High","gaps":["Structural basis of NrCAM-mediated sign conversion undefined","Whether this mechanism operates in other brain regions unknown"]},{"year":2013,"claim":"EphB2-mediated phosphorylation of NrCAM's FIGQY ankyrin-binding motif was shown to reduce ankyrin recruitment, providing a regulated switch for cytoskeletal coupling that modulates retinocollicular topographic mapping.","evidence":"EphB2 kinase assay, FIGQY mutagenesis, ankyrin recruitment in HEK293 cells, axon tracing in NrCAM/EphB null mice","pmids":["24023801"],"confidence":"High","gaps":["Whether other kinases regulate FIGQY phosphorylation in different contexts untested","Structural impact of FIGQY phosphorylation on ankyrin binding unresolved"]},{"year":2014,"claim":"Comprehensive biochemical and electrophysiological analysis showed NrCAM localizes to dendritic spines, assembles the Sema3F holoreceptor (Npn-2/PlexA3) via Ig1 TARNER motif, and controls spine density; separately, long-term nodal maintenance was shown to require both gliomedin and NrCAM.","evidence":"NrCAM null mice, co-IP of holoreceptor complex, EM, patch-clamp, rescue experiments; gliomedin/NrCAM double-null time-course","pmids":["25143608","24719088"],"confidence":"High","gaps":["Whether NrCAM spine-pruning role extends to inhibitory synapses unknown","Mechanism of ordered nodal disassembly at molecular level unresolved"]},{"year":2019,"claim":"ADAM10 was identified as the metalloprotease cleaving NrCAM, regulating its surface levels and neurite outgrowth; and conditional knockout revealed cell-autonomous NrCAM function in cortical spine pruning via a Rap-GAP/β1-integrin inactivation cascade downstream of the Sema3F holoreceptor.","evidence":"ADAM10 activation/inhibition assays, CSF proteomics; conditional inducible NrCAM KO, Rap1-GTPase and β1-integrin activity assays","pmids":["30833305","29415226"],"confidence":"High","gaps":["Whether other ADAMs contribute to NrCAM shedding in vivo untested","Temporal dynamics of Rap-GAP activation at individual spines not resolved"]},{"year":2020,"claim":"Alternative splicing of NrCAM exon 10 was linked to neuropathic pain: nerve injury increases the exon-10-included isoform, and antisense oligonucleotide-mediated splicing correction attenuates pain behaviors, revealing a non-canonical role for NrCAM isoform switching in sensory pathology.","evidence":"RNA-seq, ASO-mediated splicing shift, behavioral pain assays in mouse SNL model","pmids":["31917219"],"confidence":"High","gaps":["Mechanism by which exon 10 inclusion alters NrCAM function (binding partners, signaling) unknown","Whether exon 10 ASOs have therapeutic potential in humans untested"]},{"year":2023,"claim":"Rbfox1 was identified as an upstream splicing regulator of NrCAM exon 10 in DRG; its downregulation after nerve injury shifts NrCAM toward the pro-nociceptive L-isoform, and neurocan was shown to inhibit Sema3F-induced spine pruning by binding NrCAM.","evidence":"Lentiviral Rbfox1 gain/loss-of-function with isoform quantification and behavioral assays; ELISA binding, spine elimination assays with neurocan","pmids":["38241164","30356641"],"confidence":"High","gaps":["Direct Rbfox1 binding site on NrCAM pre-mRNA not mapped","Structural basis of neurocan–NrCAM interaction unresolved"]},{"year":2025,"claim":"NrCAM/ankyrin-B interaction was shown to maintain perisomatic CCK basket cell synapses on cortical pyramidal neurons, and a tumor-specific Δex5Δex19 NrCAM proteoform was identified as essential for pediatric high-grade glioma migration and targetable by isoform-selective antibody immunotherapy.","evidence":"NrCAM null and Ank2 conditional KO mice with CCK-BC reporter; RNA-seq, in vivo tumor assays, monoclonal antibody T-cell killing in pHGG models","pmids":["40276719","40782352"],"confidence":"High","gaps":["Whether CCK-BC synapse defects contribute to behavioral phenotypes unknown","Clinical translation of Δex5Δex19-targeting antibody not yet tested","Structural consequence of microexon deletion on NrCAM ectodomain conformation unresolved"]},{"year":null,"claim":"Major remaining questions include the atomic-resolution structure of NrCAM ectodomains and their complexes with heterophilic partners, the full inventory of isoform-specific functions across tissues, and whether NrCAM's dual roles in synapse pruning and node assembly share common signaling intermediates.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of NrCAM or its complexes available","Isoform-specific functions beyond exon 10 and Δex5Δex19 not systematically characterized","Whether spine pruning and nodal assembly share downstream signaling (e.g., ankyrin recruitment regulation) untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,3,5,6,7,9,11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,11,18,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[27,30]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[19,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8,18,22,27]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[19,29]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,11,18]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,10,12,20,21,24,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,19,30,36]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,17,23,28,33]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,3,7,9,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,34,37]}],"complexes":["Sema3F holoreceptor (NrCAM/Npn-2/PlexA3/SAP102)","Contactin/NrCAM cis-complex","Glial node complex (NrCAM/gliomedin/NF186)"],"partners":["ANK3","ANK2","CNTN1","CNTNAP1","NRP2","PLXNA3","NFASC","CNTN2"],"other_free_text":[]},"mechanistic_narrative":"NrCAM is an L1-family immunoglobulin superfamily cell adhesion molecule that mediates homophilic and heterophilic adhesion to orchestrate axon guidance, myelinated node of Ranvier assembly, dendritic spine pruning, and synapse formation in the nervous system. Its extracellular region (six Ig domains and five FNIII repeats) engages axonin-1/TAG-1, contactin/F3, neurofascin, Sema6D, RPTPβ, gliomedin, and neuropilin-2, while its cytoplasmic domain links to the actin cytoskeleton through ankyrin-G and ankyrin-B and recruits PDZ scaffolds (SAP102, PSD-95, SAP97); at nodes of Ranvier, glial NrCAM and gliomedin cluster Na⁺ channels through axonal NF186 during both initial assembly and long-term maintenance, and in cortical pyramidal neurons NrCAM assembles the Sema3F holoreceptor (Npn-2/PlexA3/SAP102) to activate PlexA3 Rap-GAP activity and prune dendritic spines [PMID:20188654, PMID:24719088, PMID:29415226, PMID:25143608]. Metalloprotease-mediated ectodomain shedding (including by ADAM10) generates a soluble NrCAM fragment that activates ERK/AKT signaling and promotes cell motility, and NrCAM is a direct transcriptional target of β-catenin/LEF-1 whose overexpression drives oncogenic transformation in melanoma, thyroid cancer, and pediatric high-grade glioma, where a tumor-specific splice variant (Δex5Δex19) is essential for migration and in vivo tumor growth [PMID:12183361, PMID:16357171, PMID:30833305, PMID:40782352]."},"prefetch_data":{"uniprot":{"accession":"Q92823","full_name":"Neuronal cell adhesion molecule","aliases":["Neuronal surface protein Bravo","hBravo","NgCAM-related cell adhesion molecule","Ng-CAM-related"],"length_aa":1304,"mass_kda":143.9,"function":"Cell adhesion protein that is required for normal responses to cell-cell contacts in brain and in the peripheral nervous system. Plays a role in neurite outgrowth in response to contactin binding. Plays a role in mediating cell-cell contacts between Schwann cells and axons. Plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons. Nodes of Ranvier contain clustered sodium channels that are crucial for the saltatory propagation of action potentials along myelinated axons. During development, nodes of Ranvier are formed by the fusion of two heminodes. Required for normal clustering of sodium channels at heminodes; not required for the formation of mature nodes with normal sodium channel clusters. Required, together with GLDN, for maintaining NFASC and sodium channel clusters at mature nodes of Ranvier","subcellular_location":"Cell membrane; Cell projection, axon; Secreted","url":"https://www.uniprot.org/uniprotkb/Q92823/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NRCAM","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/NRCAM","total_profiled":1310},"omim":[{"mim_id":"619833","title":"NEURODEVELOPMENTAL DISORDER WITH NEUROMUSCULAR AND SKELETAL ABNORMALITIES; NEDNMS","url":"https://www.omim.org/entry/619833"},{"mim_id":"619216","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 7; HMNR7","url":"https://www.omim.org/entry/619216"},{"mim_id":"614133","title":"HEPACAM FAMILY MEMBER 2; HEPACAM2","url":"https://www.omim.org/entry/614133"},{"mim_id":"609145","title":"NEUROFASCIN; NFASC","url":"https://www.omim.org/entry/609145"},{"mim_id":"608603","title":"GLIOMEDIN; GLDN","url":"https://www.omim.org/entry/608603"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":35.1},{"tissue":"brain","ntpm":101.7},{"tissue":"retina","ntpm":34.8}],"url":"https://www.proteinatlas.org/search/NRCAM"},"hgnc":{"alias_symbol":["KIAA0343","Bravo"],"prev_symbol":[]},"alphafold":{"accession":"Q92823","domains":[{"cath_id":"2.60.40.10","chopping":"45-142","consensus_level":"high","plddt":89.6552,"start":45,"end":142},{"cath_id":"2.60.40.10","chopping":"148-250","consensus_level":"medium","plddt":85.435,"start":148,"end":250},{"cath_id":"2.60.40.10","chopping":"265-359","consensus_level":"medium","plddt":91.7812,"start":265,"end":359},{"cath_id":"2.60.40.10","chopping":"367-450","consensus_level":"high","plddt":89.2995,"start":367,"end":450},{"cath_id":"2.60.40.10","chopping":"458-544","consensus_level":"high","plddt":85.0787,"start":458,"end":544},{"cath_id":"2.60.40.10","chopping":"548-633","consensus_level":"high","plddt":87.9265,"start":548,"end":633},{"cath_id":"2.60.40.10","chopping":"654-729","consensus_level":"high","plddt":90.4042,"start":654,"end":729},{"cath_id":"2.60.40.10","chopping":"752-840","consensus_level":"high","plddt":90.291,"start":752,"end":840},{"cath_id":"2.60.40.10","chopping":"854-892_900-943","consensus_level":"high","plddt":86.7905,"start":854,"end":943},{"cath_id":"2.60.40.10","chopping":"1067-1159","consensus_level":"medium","plddt":75.091,"start":1067,"end":1159}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92823","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92823-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92823-F1-predicted_aligned_error_v6.png","plddt_mean":77.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NRCAM","jax_strain_url":"https://www.jax.org/strain/search?query=NRCAM"},"sequence":{"accession":"Q92823","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92823.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92823/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92823"}},"corpus_meta":[{"pmid":"7541632","id":"PMC_7541632","title":"Axonin-1, Nr-CAM, and Ng-CAM play different roles in the in vivo guidance of chick commissural neurons.","date":"1995","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/7541632","citation_count":290,"is_preprint":false},{"pmid":"8947556","id":"PMC_8947556","title":"Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments.","date":"1996","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8947556","citation_count":285,"is_preprint":false},{"pmid":"7961622","id":"PMC_7961622","title":"Ankyrin binding activity shared by the neurofascin/L1/NrCAM family of nervous system cell adhesion molecules.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7961622","citation_count":264,"is_preprint":false},{"pmid":"2045418","id":"PMC_2045418","title":"Structure of a new nervous system glycoprotein, Nr-CAM, and 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\"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — full-length cDNA sequencing plus protein purification and N-terminal sequence confirmation in a single foundational study\",\n      \"pmids\": [\"2045418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"NrCAM mediates two distinct modes of cell adhesion: a homophilic, divalent cation-independent binding between neurons, and a heterophilic, divalent cation-dependent binding between neurons and other cell types (e.g., fibroblasts). The homophilic binding activity maps to the Ig domains and first FNIII repeat of the extracellular region.\",\n      \"method\": \"L-cell transfection aggregation assays, recombinant GST-Ig domain fusion protein (FGTNr) binding to cells and Covaspheres, antibody blocking\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with purified domains, multiple orthogonal binding assays, and functional blocking in a single rigorous study\",\n      \"pmids\": [\"1527169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"NrCAM/Bravo is a heterodimer composed of an α chain (~140/130 kD) and a β chain (60–80 kD) generated by proteolytic cleavage of an intact polypeptide at conserved Ser-Arg/Lys-Arg sites, analogous to L1 and Ng-CAM cleavage.\",\n      \"method\": \"cDNA cloning, protein biochemistry, SDS-PAGE of purified protein\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein biochemistry confirming heterodimer structure with sequence-level identification of cleavage site\",\n      \"pmids\": [\"1512296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"NrCAM/Bravo on axonal surfaces acts as a receptor for heterophilic binding to F11 (contactin family), and this interaction mediates neurite outgrowth of tectal cells. The binding site on F11 maps to the second or third Ig-like domain.\",\n      \"method\": \"Neurite outgrowth assays, antibody-blocking experiments, COS cell expression of F11 deletion mutants, cell binding assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — neurite outgrowth assay combined with domain-deletion mapping and antibody blocking, replicated in binding assays\",\n      \"pmids\": [\"8274278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The cytoplasmic domains of NrCAM (and neurofascin, L1, NgCAM, neuroglian) directly associate with ankyrins (spectrin-binding proteins), providing a membrane-cytoskeletal linkage. NrCAM and neurofascin together constitute >0.5% of membrane protein in adult brain.\",\n      \"method\": \"In vitro biochemical binding assays between purified cytoplasmic domain constructs and ankyrin, protein quantification from brain membrane fractions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical reconstitution of ankyrin binding with purified cytoplasmic domain proteins\",\n      \"pmids\": [\"7961622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In vivo, axonin-1 on commissural growth cones interacts with NrCAM on floor plate cells to guide commissural axons across the spinal cord midline; perturbation of either interaction causes commissural axons to fail to cross the midline and turn along the ipsilateral floor plate border.\",\n      \"method\": \"In vivo antibody perturbation in chick embryo spinal cord, immunohistochemistry\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo perturbation with specific antibodies producing defined guidance phenotype, highly cited foundational study\",\n      \"pmids\": [\"7541632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"NrCAM on peripheral glial cells serves as a receptor for axonin-1 on neurites, and this heterophilic interaction mediates neurite–glial cell contact formation during the early phase of axon ensheathment in dorsal root ganglia.\",\n      \"method\": \"Fluorescent microsphere binding assays with purified axonin-1 and NrCAM, antibody blocking of neurite–glia contact in DRG cultures\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — purified protein binding plus functional cell culture perturbation assays with specific antibodies\",\n      \"pmids\": [\"7490283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NrCAM and neurofascin (NF) interact heterophilically through their Ig domains; immobilized neurofascin induces neurite outgrowth of tectal cells via NrCAM on the axonal surface, while immobilized NrCAM induces neurite outgrowth via F11 (not neurofascin) as the axonal receptor. This heterophilic binding can be modulated by alternative splicing within neurofascin.\",\n      \"method\": \"Neurite outgrowth assays on immobilized substrates, antibody blocking, COS7 cell transfection binding assays, immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — reciprocal substrate assays, direct binding by immunoprecipitation, and receptor identification by antibody blocking in a single study\",\n      \"pmids\": [\"8922386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NrCAM is concentrated at the node of Ranvier and at axon initial segments, co-localizing with ankyrinG and voltage-dependent sodium channels in myelinated axons. This is the first identification of defined neuronal CAMs at nodal axon segments.\",\n      \"method\": \"Immunofluorescence localization with isoform-specific antibodies; library screen identifying rat NrCAM; co-localization with ankyrinG and Na+ channels\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization with functional context (nodal Na+ channel clustering), widely replicated\",\n      \"pmids\": [\"8947556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NrCAM and contactin form a cis complex on the neuronal surface that serves as a receptor for glial RPTPβ; binding of RPTPβ to this complex (through its carbonic anhydrase domain) promotes neurite outgrowth and neuronal differentiation.\",\n      \"method\": \"Neurite outgrowth assays, antibody blocking, co-immunoprecipitation of contactin/NrCAM complex with RPTPβ-Fc fusion proteins, NIH-3T3 surface expression of RPTPβ\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — co-IP of complex, antibody blocking of outgrowth, and cell surface expression system in a single rigorous study\",\n      \"pmids\": [\"9049255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NrCAM serves as a ligand that promotes neurite outgrowth from peripheral (DRG and sympathetic) but not central neurons, and axonin-1 functions as the neuronal receptor for NrCAM in this context; antibodies to axonin-1 block NrCAM-Fc-induced outgrowth.\",\n      \"method\": \"NrCAM-Fc substrate neurite outgrowth assays with DRG, sympathetic, tectal, and forebrain neurons; antibody blocking; in ovo injection of NrCAM-Fc causing commissural axon guidance errors\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple neuron types compared, antibody blocking identifies receptor, in vivo injection validates guidance role\",\n      \"pmids\": [\"10328925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NrCAM acts as a receptor for F3/contactin on cerebellar granule cells; F3Fc-coated microspheres bind to growth cones via NrCAM (not L1), and their retrograde movement at the growth cone is coupled to actin filament retrograde flow—disruption by cytochalasin B abolishes movement.\",\n      \"method\": \"Microsphere binding assays with antibody blocking, time-lapse video microscopy, cytochalasin B actin disruption\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging plus pharmacological actin disruption and receptor identification in a single mechanistic study\",\n      \"pmids\": [\"10462518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Axonin-1 interaction with NrCAM at the floor plate mediates commissural axon guidance (turning) without promoting axon elongation; perturbation of NrCAM + NgCAM but not either alone is required for longitudinal post-crossing growth, indicating distinct guidance and growth signals.\",\n      \"method\": \"Stripe choice assays in vitro, antibody blocking, in vivo perturbation of commissural axon pathfinding in chick embryo\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro stripe assay, in vivo genetic epistasis-like perturbation, separating guidance from growth signals\",\n      \"pmids\": [\"10811834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NrCAM null mice develop mature cataracts caused by disorganization of lens fibers accompanied by cytoskeletal abnormalities and disruption of connexin50-containing gap junctions; ankyrin-B null mice show an identical lens fiber disorganization, providing genetic evidence that NrCAM–ankyrin-B interaction is required to maintain lens fiber cell contact.\",\n      \"method\": \"NrCAM knockout mice, ankyrin-B mutant mice, histology, electron microscopy, immunostaining for connexin50 and cytoskeletal proteins\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent mutant mouse lines show identical phenotype, establishing genetic interaction between NrCAM and ankyrin-B\",\n      \"pmids\": [\"11449000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NrCAM and neurofascin function cooperatively at developing nodes of Ranvier: an NrCAM-Fc fusion protein specifically inhibits Na+ channel and ankyrinG accumulation at nodes in myelinating DRG–Schwann cell cocultures, and NrCAM-Fc clusters and co-precipitates neurofascin on axons, revealing that neurofascin plays a major role in node formation via interactions with NrCAM.\",\n      \"method\": \"Myelinating DRG–Schwann cell cocultures, NrCAM-Fc perturbation, immunofluorescence for Na+ channels and ankyrinG, co-immunoprecipitation of neurofascin by NrCAM-Fc\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional perturbation in culture plus co-IP demonstrating direct molecular interaction in a single study\",\n      \"pmids\": [\"11728309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nr-CAM-deficient cerebellar granule cells fail to extend neurites on contactin substrate in vitro, confirming contactin as an NrCAM ligand; mice doubly deficient for L1 and Nr-CAM exhibit severe cerebellar folial defects and reduced inner granule cell layer thickness not seen in either single mutant, indicating overlapping functions.\",\n      \"method\": \"NrCAM-null mouse neuronal culture, L1/NrCAM double-null mouse histology, antibody perturbation assays in cerebellar cultures\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via double knockout plus in vitro functional assay confirms ligand identity and functional redundancy\",\n      \"pmids\": [\"11564762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NrCAM is a direct transcriptional target of the β-catenin/LEF-1 pathway; LEF/TCF binding sites in the NrCAM promoter are required for its activation by β-catenin or plakoglobin; retroviral transduction of NrCAM stimulates cell growth, motility, and transformation, and anti-NrCAM antibodies inhibit melanoma cell motility.\",\n      \"method\": \"DNA microarray, promoter-reporter assays with LEF/TCF site mutations, retroviral transduction, nude mouse tumor assays, antibody blocking of motility\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter mutagenesis plus functional gain-of-function in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"12183361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In the peripheral nervous system, NrCAM (ankyrinG-binding protein) accumulates at nascent node sites prior to Na+ channels; both Na+ channel and ankyrinG sequestration at developing nodes are delayed in NrCAM null mutants, and NrCAM action is local and linked to glial contact. Computational modeling supports lateral diffusion of Na+ channels with fast cytoskeletal anchoring by ankyrinG enabled by early NrCAM arrival.\",\n      \"method\": \"NrCAM null mouse PNS, immunofluorescence during remyelination, computational diffusion-clustering model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — null mouse phenotype with quantitative immunofluorescence during development plus modeling to test mechanism\",\n      \"pmids\": [\"14602817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NrCAM coupling to the retrograde actin flow in neuroblastoma growth cones requires both the FNIII domains (for cis-interactions) and lipid raft partitioning, but not the cytoplasmic tail alone; TAG-1 bead binding induces coalescence of lipid rafts and recruitment of caveolin-1 at the adhesive contact.\",\n      \"method\": \"Optical tweezers, single particle tracking of TAG-1 beads on NrCAM deletion mutants, cholesterol depletion (methyl-β-cyclodextrin), FRAP, immunostaining for caveolin-1\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biophysical single-particle tracking combined with pharmacological manipulation and FRAP in a rigorous mechanistic study\",\n      \"pmids\": [\"15254265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NrCAM is shed from the cell surface by metalloprotease-mediated ectodomain cleavage; the shed ectodomain and conditioned medium activate ERK and AKT signaling and enhance cell motility and proliferation. NrCAM forms a complex with α4β1 integrins in melanoma cells, indicating heterophilic adhesion with extracellular matrix receptors contributes to its oncogenic function.\",\n      \"method\": \"Conditioned medium experiments, NrCAM-Fc fusion protein treatment, co-immunoprecipitation with integrins, siRNA knockdown of NrCAM, NIH3T3 transformation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP of integrin complex, metalloprotease shedding characterized, signaling pathway activation confirmed, functional rescue by secreted ectodomain\",\n      \"pmids\": [\"16357171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NrCAM promotes retinal ganglion cell (RGC) axon extension and correct pathfinding toward the optic fissure in the developing retina; NrCAM inhibition in organ-cultured eyes causes RGC axons to misroute at the optic fissure toward the opposite retinal side rather than entering the optic nerve head.\",\n      \"method\": \"Immunostaining of chick retina, substrate assays, stripe preference assays, time-lapse imaging of growth cones, antibody-blocking organ culture\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays including time-lapse imaging and organ-culture perturbation with specific antibodies\",\n      \"pmids\": [\"16033798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NrCAM expressed on contralaterally-projecting retinal ganglion cells is critical for guidance of late-born RGCs through the optic chiasm; blocking NrCAM function increases the ipsilateral projection and reduces neurite outgrowth on chiasm cells in an age- and region-specific manner. EphB1/ephrin-B2-mediated repulsion and NrCAM-mediated attraction represent distinct molecular programs for binocular visual pathway formation.\",\n      \"method\": \"NrCAM null mice, anterograde axon tracing, in vitro neurite outgrowth on chiasm cells with antibody blocking\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — null mouse in vivo tracing plus in vitro functional assay, identifying NrCAM-attraction as distinct from EphB-repulsion\",\n      \"pmids\": [\"16701205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The cytoplasmic C-terminus of NrCAM contains a PDZ-binding motif that specifically interacts with class I PDZ domains of the scaffold proteins SAP90/PSD-95 and SAP97; this interaction recruits SAP97 to the plasma membrane and is distinct from L1, CHL1, and neurofascin.\",\n      \"method\": \"Pull-down assays with cytoplasmic domain constructs, co-transfection of COS-7 cells, co-localization in photoreceptor terminals\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical pull-down confirming direct PDZ interaction, functional recruitment assay in cells, and co-localization in tissue\",\n      \"pmids\": [\"16882004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In the peripheral nervous system, glial NrCAM and gliomedin together act through axonal neurofascin 186 (NF186) to cluster Na+ channels at heminodes during early node of Ranvier formation; a second paranodal junction-dependent mechanism then concentrates Na+ channels at mature nodes by restricting their diffusion.\",\n      \"method\": \"NrCAM and gliomedin null mice, immunofluorescence during PNS myelination, electron microscopy\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — null mouse analysis during development, mechanistic dissection of two cooperative clustering mechanisms, highly cited\",\n      \"pmids\": [\"20188654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NrCAM forms a molecular complex with neuropilin-2 (Npn-2) in brain and neurons, and is required for Sema3F-induced growth cone collapse in thalamic neurons; NrCAM deletion causes mistargeting of thalamocortical axons to visual cortex and disrupts visual acuity.\",\n      \"method\": \"NrCAM null mice, Npn-2 null mice, anterograde axon tracing, co-immunoprecipitation of NrCAM–Npn-2 complex, growth cone collapse assay in thalamic neuron cultures\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP of complex, null mouse phenotype with axon tracing, functional growth cone collapse assay, multiple orthogonal methods\",\n      \"pmids\": [\"21273439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sema6D and NrCAM are expressed on midline radial glia while Plexin-A1 and NrCAM are expressed on contralateral RGCs; NrCAM functions as a receptor for Sema6D, and a tripartite Sema6D/Nr-CAM/Plexin-A1 complex converts Sema6D repulsion to growth promotion, enabling RGC decussation at the optic chiasm.\",\n      \"method\": \"In situ hybridization and immunostaining of optic chiasm, RGC-specific perturbation, in vitro growth assays, receptor-ligand binding assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor identification, complex characterization, in vitro and in vivo functional assays defining sign-conversion mechanism\",\n      \"pmids\": [\"22632726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NrCAM contributes to mediolateral retinocollicular axon targeting; EphB2 tyrosine kinase phosphorylates NrCAM at a conserved tyrosine in the FIGQY ankyrin-binding motif, reducing ankyrin recruitment and modulating linkage of NrCAM to the actin cytoskeleton. Phospho-FIGQY levels of NrCAM in SC correlate with EphB activity in multiple mutant mouse backgrounds.\",\n      \"method\": \"EphB2 kinase phosphorylation assay, mutagenesis of FIGQY site, ankyrin recruitment in HEK293 cells, anterograde RGC axon tracing in NrCAM and EphB null mice, phospho-FIGQY immunostaining\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — kinase assay with mutagenesis, functional ankyrin recruitment assay, validated in multiple mouse mutant backgrounds\",\n      \"pmids\": [\"24023801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NrCAM localizes to dendritic spines of cortical pyramidal neurons and forms a complex with Sema3F receptor subunits Neuropilin-2 (Npn-2) and PlexinA3 (PlexA3) through an Npn-2-binding sequence (TARNER) in its extracellular Ig1 domain; NrCAM deletion elevates spine densities and increases mEPSC frequency, and re-expression of NrCAM rescues Sema3F-induced spine retraction.\",\n      \"method\": \"NrCAM null mice, co-immunoprecipitation, electron microscopy, whole-cell patch-clamp recordings, rescue experiments with NrCAM re-expression, trans-heterozygous genetic interaction test\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — co-IP defining complex, electrophysiology, EM, rescue experiment, and genetic epistasis in a single comprehensive study\",\n      \"pmids\": [\"25143608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Long-term maintenance of Na+ channels at nodes of Ranvier requires continued axon-glial contact mediated by both gliomedin and NrCAM together; mice lacking both molecules show gradual loss of Na+ channels, NF186, ankyrinG, and βIV spectrin from nodes in an ordered sequence mirroring assembly, formation of binary nodes, and Schwann cell invasion of the nodal gap.\",\n      \"method\": \"Gliomedin/NrCAM double null mice, immunofluorescence time-course, electrophysiology (nerve conduction), electron microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double null mouse with detailed temporal immunofluorescence, electrophysiology, and EM revealing ordered disassembly mechanism\",\n      \"pmids\": [\"24719088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NrCAM is a substrate of ADAM10; ADAM10 controls NrCAM surface levels and regulates neurite outgrowth in an NrCAM-dependent manner in vitro. Unlike APP, ADAM10 cleavage of NrCAM is not stimulated by the ADAM10 activator acitretin, demonstrating substrate-selective ADAM10 activation.\",\n      \"method\": \"ADAM10 activation/inhibition assays, NrCAM surface level measurement, neurite outgrowth assays, CSF proteomics from clinical trial samples\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assay with ADAM10 manipulations, NrCAM-dependence confirmed, validated in human CSF proteomics\",\n      \"pmids\": [\"30833305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NrCAM acts cell-autonomously in adolescent cortical pyramidal neurons to limit dendritic spine density; it promotes clustering of the Sema3F holoreceptor (Npn-2/PlexA3) by interfacing with Npn-2 and PDZ scaffold SAP102, thereby stimulating PlexA3 Rap-GAP activity, inhibiting Rap1-GTPase, and inactivating adhesive β1 integrins to drive Sema3F-induced spine pruning.\",\n      \"method\": \"Conditional inducible NrCAM knockout mice (Nex1Cre-ERT2:NrCAMflox/flox), molecular modeling, co-immunoprecipitation of holoreceptor complex, Rap1-GTPase and β1-integrin activity assays\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — inducible cell-autonomous KO, biochemical signaling cascade delineated by co-IP and GTPase assays in a single study\",\n      \"pmids\": [\"29415226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Neurocan (a chondroitin sulfate proteoglycan) inhibits Sema3F-induced spine elimination by physically associating with NrCAM; glycosaminoglycan chain interactions of neurocan are required for this inhibitory effect on the NrCAM/Npn-2/PlexA3 Sema3F holoreceptor complex.\",\n      \"method\": \"ELISA binding assays, COS-7 cell morphological retraction assay, antibody blocking, spine elimination assay in cortical neuron cultures, immunoelectron microscopy\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay, functional cell assay with domain-deletion analysis, EM localization\",\n      \"pmids\": [\"30356641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Alternative splicing of Nrcam exon 10 in dorsal root ganglia contributes to neuropathic pain; spinal nerve ligation increases exon 10 insertion (Nrcam+10 isoform), and antisense oligonucleotides targeting exon 10 that shift splicing toward the Nrcam-10 isoform attenuate mechanical allodynia, thermal hyperalgesia, and cold allodynia in mice.\",\n      \"method\": \"RNA-seq, antisense oligonucleotide splicing manipulation, DRG microinjection, intrathecal injection, behavioral pain assays (von Frey, Hargreaves, acetone) in mice\",\n      \"journal\": \"The journal of pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq identification, ASO-mediated isoform switching with in vivo behavioral rescue, validated in two pain models\",\n      \"pmids\": [\"31917219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NrCAM and Ankyrin B mediate perisomatic synaptic contact between cholecystokinin (CCK) basket interneurons and pyramidal neurons in mouse medial prefrontal cortex; NrCAM null mice show a significant decrease in CCK-BC (but not PV-BC) synaptic puncta on PN soma, and Ankyrin B deletion from PNs phenocopies this loss.\",\n      \"method\": \"NrCAM null mice, Ankyrin B conditional knockout (Nex1Cre-ERT2:Ank2flox/flox), VGLUT3/VGAT immunolabeling, CCK-BC reporter mouse (Sncg-tdT), NrCAM co-localization with Sncg+ CCK-BCs\",\n      \"journal\": \"Current research in neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent genetic deletions (NrCAM null and Ankyrin B conditional KO) converging on same synaptic phenotype, with reporter mouse for CCK-BC identification\",\n      \"pmids\": [\"40276719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A tumor-specific NrCAM proteoform lacking microexons 5 and 19 (Δex5Δex19 NRCAM) is uniformly expressed in pediatric high-grade gliomas; this proteoform (but not full-length NrCAM) is essential for pHGG cell migration and invasion in vitro and tumor growth in vivo, and a monoclonal antibody selective for Δex5Δex19 NrCAM enables T-cell-mediated tumor killing.\",\n      \"method\": \"Bulk and single-nuclei RNA-seq (short- and long-read), in vitro migration/invasion assays, in vivo tumor growth assays, monoclonal antibody development, FcRI-based universal immune receptor T-cell killing assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — loss-of-function in vitro and in vivo, isoform-specific antibody, and T-cell killing assay in a single comprehensive study\",\n      \"pmids\": [\"40782352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rbfox1 (an RNA-binding protein) regulates alternative splicing of NrCAM exon 10 in dorsal root ganglia; peripheral nerve injury downregulates Rbfox1, increasing L-Nrcam (exon 10-included) variants; restoring Rbfox1 reduces nociceptive hypersensitivity, while mimicking its downregulation induces neuropathic pain.\",\n      \"method\": \"Transcriptome profiling of DRG after SNL, bioinformatics, lentiviral Rbfox1 overexpression and knockdown, RT-PCR isoform quantification, behavioral pain assays\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function of splicing regulator with direct measurement of NrCAM isoform ratios and behavioral validation\",\n      \"pmids\": [\"38241164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NrCAM activates MAPK/ERK and PI3K/AKT signaling pathways in thyroid cancer via ectodomain shedding and binding to EGFR and α4β1 integrins; in turn, these pathways drive NrCAM overexpression through the GSK3β/β-catenin axis, forming a positive feedback loop.\",\n      \"method\": \"NrCAM knockdown/overexpression in thyroid cancer cells, co-immunoprecipitation with EGFR and integrins, in vivo nude mouse xenografts, BrafV600E transgenic mice\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP of receptor complexes plus in vivo validation, but signaling pathway attribution relies on standard inhibitor experiments in a single lab\",\n      \"pmids\": [\"27732334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In hepatocellular carcinoma liver cancer stem cells, NrCAM activates EMT and metastasis-related MMPs through the MACF1-mediated β-catenin signaling pathway, facilitating intra-hepatic and lung metastasis.\",\n      \"method\": \"NrCAM inhibition in MYC-driven LCSC organoids, in vivo tumor allografts, scRNA-seq, co-immunoprecipitation/pathway analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro and in vivo evidence with mechanistic pathway (MACF1/β-catenin) identified, single lab study\",\n      \"pmids\": [\"37993901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Alternative splicing of Nrcam exon 10 regulates neurite outgrowth of DRG neurons; antisense oligonucleotides targeting exon 10 (shifting toward short Nrcam variants) suppress neurite length in multiple DRG neuron subtypes via activation of EGFR signaling.\",\n      \"method\": \"DRG primary culture, Nrcam ASO treatment, immunostaining with DRG subtype markers, EGFR activation assays\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, ASO manipulation with immunostaining and signaling marker, no direct isoform rescue experiment\",\n      \"pmids\": [\"33850082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NrCAM secreted by endometrial stromal cells increases progestin sensitivity of endometrial cancer cells by upregulating PRB through TET1-induced hydroxymethylation of the PRB gene promoter region.\",\n      \"method\": \"Co-culture experiments, NrCAM ELISA in conditioned medium, nude mouse xenografts with MPA±NrCAM, TET1 knockdown, bisulfite sequencing of PRB promoter hydroxymethylation\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct mechanistic link (TET1-mediated PRB hydroxymethylation) plus in vivo validation, single lab\",\n      \"pmids\": [\"35388173\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NrCAM is an L1-family Ig/FNIII cell adhesion molecule that mediates homophilic and heterophilic adhesion (with axonin-1/TAG-1, contactin/F3, neurofascin, Sema6D, gliomedin, RPTPβ, EGFR, and α4β1 integrins) and links extracellular signals to the actin cytoskeleton via its cytoplasmic domain interactions with ankyrin (G and B) and PDZ scaffold proteins (SAP90/PSD-95, SAP97); at the node of Ranvier, glial NrCAM and gliomedin cluster Na+ channels through axonal NF186 both during development and for long-term maintenance, while in cortical neurons NrCAM assembles the Sema3F holoreceptor complex (Npn-2/PlexA3/SAP102) to activate PlexA3 Rap-GAP activity and prune dendritic spines, and its ectodomain shedding by metalloproteases (including ADAM10) generates a soluble ligand that activates ERK/AKT signaling to promote cell motility and oncogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NrCAM is an L1-family immunoglobulin superfamily cell adhesion molecule that mediates homophilic and heterophilic adhesion to orchestrate axon guidance, myelinated node of Ranvier assembly, dendritic spine pruning, and synapse formation in the nervous system. Its extracellular region (six Ig domains and five FNIII repeats) engages axonin-1/TAG-1, contactin/F3, neurofascin, Sema6D, RPTPβ, gliomedin, and neuropilin-2, while its cytoplasmic domain links to the actin cytoskeleton through ankyrin-G and ankyrin-B and recruits PDZ scaffolds (SAP102, PSD-95, SAP97); at nodes of Ranvier, glial NrCAM and gliomedin cluster Na⁺ channels through axonal NF186 during both initial assembly and long-term maintenance, and in cortical pyramidal neurons NrCAM assembles the Sema3F holoreceptor (Npn-2/PlexA3/SAP102) to activate PlexA3 Rap-GAP activity and prune dendritic spines [PMID:20188654, PMID:24719088, PMID:29415226, PMID:25143608]. Metalloprotease-mediated ectodomain shedding (including by ADAM10) generates a soluble NrCAM fragment that activates ERK/AKT signaling and promotes cell motility, and NrCAM is a direct transcriptional target of β-catenin/LEF-1 whose overexpression drives oncogenic transformation in melanoma, thyroid cancer, and pediatric high-grade glioma, where a tumor-specific splice variant (Δex5Δex19) is essential for migration and in vivo tumor growth [PMID:12183361, PMID:16357171, PMID:30833305, PMID:40782352].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification of NrCAM as a new neural Ig/FNIII cell adhesion molecule with alternative splicing established a foundational structural framework for understanding L1-family adhesion in the nervous system.\",\n      \"evidence\": \"cDNA cloning, protein purification, SDS-PAGE, Northern/Southern blotting from chick brain\",\n      \"pmids\": [\"2045418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure not determined\", \"Functional significance of individual splice variants unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstration that NrCAM mediates both homophilic (cation-independent) and heterophilic (cation-dependent) cell adhesion, with homophilic binding mapped to Ig domains and first FNIII repeat, established dual adhesion modalities and identified the first functional domains.\",\n      \"evidence\": \"L-cell transfection aggregation assays, recombinant GST-domain fusion binding, antibody blocking\",\n      \"pmids\": [\"1527169\", \"1512296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of heterophilic ligands unknown\", \"Structural basis of cation-dependent vs. cation-independent adhesion unresolved\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Discovery that contactin-family F11 on neurons binds NrCAM heterophilically to promote neurite outgrowth identified the first trans-heterophilic partner and linked NrCAM to axon growth signaling.\",\n      \"evidence\": \"Neurite outgrowth assays, COS cell F11 deletion mutants, antibody blocking\",\n      \"pmids\": [\"8274278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling cascade downstream of NrCAM–F11 interaction undefined\", \"Whether this is a general or context-specific interaction unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Biochemical demonstration that NrCAM's cytoplasmic domain directly binds ankyrins established the membrane-cytoskeleton linkage mechanism shared across the L1 family.\",\n      \"evidence\": \"In vitro binding assays between purified cytoplasmic domains and ankyrin\",\n      \"pmids\": [\"7961622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of ankyrin binding (e.g., by phosphorylation) not yet addressed\", \"Functional consequence of ankyrin association in vivo untested\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"In vivo antibody perturbation showed that axonin-1/NrCAM interaction at the floor plate is required for commissural axon midline crossing, providing the first in vivo guidance function for NrCAM.\",\n      \"evidence\": \"Anti-NrCAM and anti-axonin-1 antibody injection in chick embryo spinal cord with immunohistochemistry\",\n      \"pmids\": [\"7541632\", \"7490283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling triggered by axonin-1–NrCAM binding at the floor plate not characterized\", \"Redundancy with other L1-family members at midline untested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Localization of NrCAM to nodes of Ranvier with ankyrinG and Na⁺ channels, plus demonstration of reciprocal NrCAM–neurofascin heterophilic interactions modulated by splicing, established NrCAM as a key nodal organizer and defined a second major heterophilic partner.\",\n      \"evidence\": \"Immunofluorescence at nodes/axon initial segments; neurite outgrowth substrate assays and co-immunoprecipitation of neurofascin–NrCAM\",\n      \"pmids\": [\"8947556\", \"8922386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NrCAM is required for Na⁺ channel clustering at nodes not yet tested genetically\", \"Mechanism of NrCAM initial targeting to nodes unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of a cis contactin/NrCAM complex as a neuronal receptor for glial RPTPβ linked NrCAM to receptor phosphatase signaling and demonstrated a tripartite signaling complex promoting neurite outgrowth.\",\n      \"evidence\": \"Co-immunoprecipitation of contactin/NrCAM with RPTPβ-Fc; antibody-blocking neurite outgrowth assays\",\n      \"pmids\": [\"9049255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase substrates downstream of RPTPβ at the NrCAM complex unknown\", \"Stoichiometry of the tripartite complex unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"NrCAM knockout mice revealed a non-neural requirement: NrCAM–ankyrin-B interaction maintains lens fiber cell organization, with loss causing cataracts; separately, NrCAM-Fc perturbation and double-knockout with L1 demonstrated cooperative roles in node of Ranvier formation and cerebellar development.\",\n      \"evidence\": \"NrCAM null mice, ankyrin-B null mice, DRG–Schwann cell myelinating cocultures, L1/NrCAM double null histology\",\n      \"pmids\": [\"11449000\", \"11728309\", \"11564762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of NrCAM–ankyrin-B specificity vs. ankyrin-G at nodes not resolved\", \"Whether cataract phenotype reflects a broader non-neural adhesion role unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of NrCAM as a direct β-catenin/LEF-1 transcriptional target whose overexpression drives cell motility, growth, and transformation established NrCAM as a Wnt pathway effector gene with oncogenic potential.\",\n      \"evidence\": \"Promoter-reporter assays with LEF/TCF site mutations, retroviral transduction, nude mouse tumor assays\",\n      \"pmids\": [\"12183361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where Wnt-driven NrCAM upregulation is relevant beyond melanoma not yet explored\", \"Whether NrCAM oncogenic activity requires specific splice isoforms unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Analysis of NrCAM null mice during PNS development showed NrCAM arrives at nascent nodes before Na⁺ channels and is needed for efficient ankyrinG/Na⁺ channel clustering, establishing a temporal hierarchy in node assembly.\",\n      \"evidence\": \"NrCAM null mouse PNS immunofluorescence during remyelination, computational diffusion-clustering model\",\n      \"pmids\": [\"14602817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NrCAM's role in CNS node formation less clear\", \"Direct visualization of Na⁺ channel lateral diffusion trapping not achieved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Biophysical analysis revealed that NrCAM coupling to retrograde actin flow requires FNIII-mediated cis-interactions and lipid raft partitioning rather than the cytoplasmic tail alone, redefining the force-transmission mechanism.\",\n      \"evidence\": \"Optical tweezers and single-particle tracking of TAG-1 beads on NrCAM deletion mutants in neuroblastoma growth cones\",\n      \"pmids\": [\"15254265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cis-interacting partner in lipid rafts not fully resolved\", \"Whether this mechanism operates at nodes of Ranvier untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery of metalloprotease-mediated NrCAM ectodomain shedding generating a soluble fragment that activates ERK/AKT and promotes motility, plus identification of α4β1 integrin as a co-receptor, revealed the signaling mechanism underlying NrCAM's oncogenic activity.\",\n      \"evidence\": \"NrCAM-Fc treatment, conditioned medium experiments, co-immunoprecipitation with integrins, siRNA knockdown, NIH3T3 transformation\",\n      \"pmids\": [\"16357171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the metalloprotease responsible not determined at this stage\", \"Structural basis of NrCAM–integrin interaction unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Functional studies in retina showed NrCAM promotes RGC axon extension and correct pathfinding at the optic fissure, extending its guidance role to the visual system.\",\n      \"evidence\": \"Antibody-blocking organ culture of chick retina, time-lapse imaging, stripe preference assays\",\n      \"pmids\": [\"16033798\", \"16701205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling in RGC growth cones not defined\", \"Relative contribution of NrCAM vs. other cues at the optic chiasm not quantified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of NrCAM's C-terminal PDZ-binding motif interaction with SAP90/PSD-95 and SAP97 provided a scaffold-coupling mechanism distinct from the ankyrin linkage, expanding the repertoire of cytoplasmic signaling outputs.\",\n      \"evidence\": \"Pull-down assays with cytoplasmic domain constructs, COS-7 co-transfection, co-localization in photoreceptor terminals\",\n      \"pmids\": [\"16882004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of NrCAM–PSD-95 interaction at synapses not established\", \"Whether PDZ and ankyrin binding are mutually exclusive or cooperative unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Double-null mouse analysis established that glial NrCAM and gliomedin cooperate through axonal NF186 for initial Na⁺ channel clustering at heminodes, with a second paranodal mechanism acting at mature nodes, resolving the cooperative mechanism of node assembly.\",\n      \"evidence\": \"NrCAM and gliomedin null mice, developmental immunofluorescence in PNS, electron microscopy\",\n      \"pmids\": [\"20188654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CNS node formation mechanism by NrCAM less defined\", \"Whether NrCAM acts as a direct ligand for NF186 or only through gliomedin unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that NrCAM functions as a Sema6D receptor and forms a tripartite Sema6D/NrCAM/PlexA1 complex that converts repulsion to growth promotion at the optic chiasm revealed a novel sign-conversion mechanism in axon guidance.\",\n      \"evidence\": \"Receptor-ligand binding, in vitro growth assays, RGC-specific perturbation at the optic chiasm\",\n      \"pmids\": [\"22632726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NrCAM-mediated sign conversion undefined\", \"Whether this mechanism operates in other brain regions unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"EphB2-mediated phosphorylation of NrCAM's FIGQY ankyrin-binding motif was shown to reduce ankyrin recruitment, providing a regulated switch for cytoskeletal coupling that modulates retinocollicular topographic mapping.\",\n      \"evidence\": \"EphB2 kinase assay, FIGQY mutagenesis, ankyrin recruitment in HEK293 cells, axon tracing in NrCAM/EphB null mice\",\n      \"pmids\": [\"24023801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases regulate FIGQY phosphorylation in different contexts untested\", \"Structural impact of FIGQY phosphorylation on ankyrin binding unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Comprehensive biochemical and electrophysiological analysis showed NrCAM localizes to dendritic spines, assembles the Sema3F holoreceptor (Npn-2/PlexA3) via Ig1 TARNER motif, and controls spine density; separately, long-term nodal maintenance was shown to require both gliomedin and NrCAM.\",\n      \"evidence\": \"NrCAM null mice, co-IP of holoreceptor complex, EM, patch-clamp, rescue experiments; gliomedin/NrCAM double-null time-course\",\n      \"pmids\": [\"25143608\", \"24719088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NrCAM spine-pruning role extends to inhibitory synapses unknown\", \"Mechanism of ordered nodal disassembly at molecular level unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ADAM10 was identified as the metalloprotease cleaving NrCAM, regulating its surface levels and neurite outgrowth; and conditional knockout revealed cell-autonomous NrCAM function in cortical spine pruning via a Rap-GAP/β1-integrin inactivation cascade downstream of the Sema3F holoreceptor.\",\n      \"evidence\": \"ADAM10 activation/inhibition assays, CSF proteomics; conditional inducible NrCAM KO, Rap1-GTPase and β1-integrin activity assays\",\n      \"pmids\": [\"30833305\", \"29415226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other ADAMs contribute to NrCAM shedding in vivo untested\", \"Temporal dynamics of Rap-GAP activation at individual spines not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Alternative splicing of NrCAM exon 10 was linked to neuropathic pain: nerve injury increases the exon-10-included isoform, and antisense oligonucleotide-mediated splicing correction attenuates pain behaviors, revealing a non-canonical role for NrCAM isoform switching in sensory pathology.\",\n      \"evidence\": \"RNA-seq, ASO-mediated splicing shift, behavioral pain assays in mouse SNL model\",\n      \"pmids\": [\"31917219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which exon 10 inclusion alters NrCAM function (binding partners, signaling) unknown\", \"Whether exon 10 ASOs have therapeutic potential in humans untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Rbfox1 was identified as an upstream splicing regulator of NrCAM exon 10 in DRG; its downregulation after nerve injury shifts NrCAM toward the pro-nociceptive L-isoform, and neurocan was shown to inhibit Sema3F-induced spine pruning by binding NrCAM.\",\n      \"evidence\": \"Lentiviral Rbfox1 gain/loss-of-function with isoform quantification and behavioral assays; ELISA binding, spine elimination assays with neurocan\",\n      \"pmids\": [\"38241164\", \"30356641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Rbfox1 binding site on NrCAM pre-mRNA not mapped\", \"Structural basis of neurocan–NrCAM interaction unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"NrCAM/ankyrin-B interaction was shown to maintain perisomatic CCK basket cell synapses on cortical pyramidal neurons, and a tumor-specific Δex5Δex19 NrCAM proteoform was identified as essential for pediatric high-grade glioma migration and targetable by isoform-selective antibody immunotherapy.\",\n      \"evidence\": \"NrCAM null and Ank2 conditional KO mice with CCK-BC reporter; RNA-seq, in vivo tumor assays, monoclonal antibody T-cell killing in pHGG models\",\n      \"pmids\": [\"40276719\", \"40782352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCK-BC synapse defects contribute to behavioral phenotypes unknown\", \"Clinical translation of Δex5Δex19-targeting antibody not yet tested\", \"Structural consequence of microexon deletion on NrCAM ectodomain conformation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major remaining questions include the atomic-resolution structure of NrCAM ectodomains and their complexes with heterophilic partners, the full inventory of isoform-specific functions across tissues, and whether NrCAM's dual roles in synapse pruning and node assembly share common signaling intermediates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of NrCAM or its complexes available\", \"Isoform-specific functions beyond exon 10 and Δex5Δex19 not systematically characterized\", \"Whether spine pruning and nodal assembly share downstream signaling (e.g., ankyrin recruitment regulation) untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 3, 5, 6, 7, 9, 11]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 11, 18, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [27, 30]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [19, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8, 18, 22, 27]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [19, 29]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 11, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 10, 12, 20, 21, 24, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 19, 30, 36]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 17, 23, 28, 33]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 3, 7, 9, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 34, 37]}\n    ],\n    \"complexes\": [\n      \"Sema3F holoreceptor (NrCAM/Npn-2/PlexA3/SAP102)\",\n      \"Contactin/NrCAM cis-complex\",\n      \"Glial node complex (NrCAM/gliomedin/NF186)\"\n    ],\n    \"partners\": [\n      \"ANK3\",\n      \"ANK2\",\n      \"CNTN1\",\n      \"CNTNAP1\",\n      \"NRP2\",\n      \"PLXNA3\",\n      \"NFASC\",\n      \"CNTN2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}