{"gene":"NRCAM","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1991,"finding":"Nr-CAM (NrCAM) was identified as a novel neural glycoprotein with a structure comprising six Ig-like domains, five fibronectin type III repeats, a transmembrane domain, and a short cytoplasmic domain, encoded by a single gene with alternatively spliced mRNAs. Purified protein (Mr 145,000) was confirmed by N-terminal sequencing matching the cDNA-predicted sequence.","method":"cDNA cloning, protein purification by lentil lectin affinity chromatography/FPLC, N-terminal sequencing, Northern and Southern blotting","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — full-length cDNA sequencing, protein purification with biochemical verification; foundational structural characterization replicated by subsequent studies","pmids":["2045418"],"is_preprint":false},{"year":1992,"finding":"NrCAM (Bravo) mediates both homophilic (divalent cation-independent) and heterophilic (divalent cation-dependent) cell adhesion. Homophilic binding was demonstrated between transfected L cells and between cells and recombinant FGTNr (Ig domains 1-6 + first FNIII repeat fusion protein). Heterophilic binding occurred between NrCAM-transfected and untransfected L cells and between FGTNr and fibroblasts.","method":"Cell aggregation assay, substrate binding assay, Covasphere aggregation assay, recombinant fusion protein (FGTNr) inhibition, L-cell transfection","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro binding assays with recombinant proteins, transfected cells, and inhibitory reagents; replicated across systems","pmids":["1527169"],"is_preprint":false},{"year":1992,"finding":"Bravo/NrCAM has a heterodimer structure composed of an alpha chain (Mr 140/130 kD) and a beta chain (60-80 kD) generated by cleavage of an intact polypeptide at a conserved Ser-Arg/Lys-Arg site, analogous to L1 and Ng-CAM. The molecule contains alternatively spliced sequences encoding both extra- and intracellular stretches.","method":"cDNA cloning, SDS-PAGE, sequence analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization with cDNA and protein analysis, single lab but consistent with parallel L1/NgCAM findings","pmids":["1512296"],"is_preprint":false},{"year":1993,"finding":"Neurite extension of tectal cells on immobilized F11 (contactin) is mediated by NrCAM/Bravo on the axonal surface. Direct heterophilic binding between F11 and NrCAM/Bravo was demonstrated, and the interaction was mapped to the second or third Ig-like domain of F11 using domain-specific monoclonal antibodies and deletion mutant proteins expressed on COS cells.","method":"Neurite outgrowth assay, antibody blocking, COS cell binding assay, deletion mutants","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — neurite outgrowth functional assay combined with direct binding and domain mapping; multiple orthogonal approaches","pmids":["8274278"],"is_preprint":false},{"year":1994,"finding":"The cytoplasmic domains of NrCAM (along with neurofascin, L1, NgCAM, and neuroglian) directly associate with ankyrins. NrCAM and neurofascin together comprise over 0.5% of total membrane protein in adult brain tissue, indicating this ankyrin linkage is a major membrane-cytoskeletal connection.","method":"Biochemical co-association assay, protein quantification from brain membrane fractions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical demonstration of ankyrin binding via cytoplasmic domain; replicated independently by node of Ranvier localization studies","pmids":["7961622"],"is_preprint":false},{"year":1995,"finding":"In vivo perturbation experiments in chick showed that the interaction between axonin-1 on commissural growth cones and Nr-CAM on floor plate cells is required for accurate midline pathfinding. When axonin-1 or Nr-CAM interactions were perturbed (by antibody injection), many commissural axons failed to cross the midline and turned along the ipsilateral floor plate border instead.","method":"In vivo antibody perturbation in chick embryo spinal cord, histological analysis of axon trajectories","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct in vivo loss-of-function with specific phenotypic readout; foundational guidance study independently replicated","pmids":["7541632"],"is_preprint":false},{"year":1995,"finding":"Axonin-1 binds directly to NrCAM on peripheral glial cells, mediating neuron-glia contacts. Fluorescent microspheres conjugated with axonin-1 bound to glial cells via NrCAM (identified by antibody blockage). Anti-axonin-1 and anti-NrCAM antibodies both perturbed neurite-glia contact formation in dissociated DRG cultures, implicating this interaction in early axon ensheathment.","method":"Microsphere binding assay, antibody blocking, purified protein binding assay, dissociated DRG neuron-glia culture perturbation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal binding and functional assays; direct interaction confirmed with purified proteins","pmids":["7490283"],"is_preprint":false},{"year":1996,"finding":"NrCAM and a specific isoform of neurofascin (mucin+/third FNIII domain-) are colocalized with ankyrinG and voltage-dependent sodium channels at nodes of Ranvier and axon initial segments. NrCAM was identified by screening a rat brain cDNA expression library with anti-neurofascin antibody; it shares >70% cytoplasmic domain identity with neurofascin.","method":"cDNA library screening, isoform-specific antibody generation, immunofluorescence co-localization, cDNA sequencing","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization with isoform-specific antibodies; replicated by multiple independent groups at nodes of Ranvier","pmids":["8947556"],"is_preprint":false},{"year":1996,"finding":"Neurofascin promotes neurite extension from tectal cells by heterophilic interaction with NrCAM on axonal surfaces. Conversely, when NrCAM is the substrate, it induces neurite extension through F11 (not neurofascin) as the axonal receptor. Direct binding between neurofascin and NrCAM was demonstrated by transfected COS7 cell binding and immunoprecipitation, and mapped to the Ig domains of neurofascin. Alternative splicing of neurofascin modulates this binding.","method":"Neurite outgrowth assay on immobilized substrates, antibody blocking, COS7 cell transfection binding assay, immunoprecipitation, deletion mapping","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding assays, immunoprecipitation, domain mapping, functional neurite assays in one study","pmids":["8922386"],"is_preprint":false},{"year":1997,"finding":"The extracellular region of glial receptor protein tyrosine phosphatase beta (RPTPbeta) binds to a complex of contactin and NrCAM on neurons. Neurite outgrowth induced by betaCFS (RPTPbeta fusion) was inhibited by antibodies against both NrCAM and contactin, and contactin/NrCAM co-immunoprecipitated with betaCFS. NIH-3T3 cells expressing betaCFS on their surfaces induced neuronal differentiation.","method":"Antibody blocking of neurite outgrowth, co-immunoprecipitation, recombinant fusion proteins, transfected cell co-culture assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP of complex, functional blocking, and cell-based differentiation assay in one study; multiple orthogonal approaches","pmids":["9049255"],"is_preprint":false},{"year":1999,"finding":"NrCAM functions as a substrate ligand for neurite outgrowth from dorsal root ganglion (DRG) and sympathetic ganglion neurons via axonin-1 as the neuronal receptor. A recombinant Nr-CAM-Fc fusion protein (containing all 6 Ig domains and first 2 FNIII repeats) promoted neurite outgrowth from peripheral but not central neurons; anti-axonin-1 antibodies inhibited this outgrowth. In ovo injection of Nr-Fc produced commissural axon guidance errors similar to anti-axonin-1 treatment.","method":"Recombinant Fc fusion protein substrate assay, antibody blocking of neurite outgrowth, in ovo injection, immunostaining","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro functional assay with defined recombinant protein plus in vivo confirmation; multiple approaches","pmids":["10328925"],"is_preprint":false},{"year":1999,"finding":"NrCAM is the functional receptor on cerebellar granule cells for the neuronal adhesion glycoprotein F3 (contactin). F3Fc-conjugated microspheres bound growth cones via NrCAM (not L1). These beads moved retrogradely at 5.7 µm/min (actin retrograde flow velocity); cytochalasin B (actin disruptor) abolished this movement. NrCAM clustering (induced by cross-linked F3Fc) was required for retrograde mobility.","method":"Microsphere binding assay, time-lapse video microscopy, cytochalasin B treatment, single particle tracking","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding identification, live-cell imaging, pharmacological perturbation, mechanistic coupling to actin cytoskeleton demonstrated","pmids":["10462518"],"is_preprint":false},{"year":2000,"finding":"Axonin-1 interaction with floor-plate NrCAM mediates commissural axon guidance (directionality) without promoting axon elongation. In stripe assays, commissural axons preferred NrCAM+NgCAM stripes; anti-axonin-1 abolished this preference without reducing neurite length. In vivo, axonin-1/NrCAM perturbation selectively caused guidance failure, not elongation defects.","method":"In vitro stripe assay, antibody blocking, in vivo perturbation with phenotypic measurement of guidance vs. elongation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection of guidance vs. elongation using orthogonal in vitro and in vivo approaches; clear functional discrimination","pmids":["10811834"],"is_preprint":false},{"year":2001,"finding":"Nr-CAM interacts with Nr-CAM-Fc fusion protein and with neurofascin on axonal surfaces to cluster neurofascin and co-precipitate it. Treatment of myelinating DRG-Schwann cell cocultures with Nr-CAM-Fc fusion protein specifically inhibited Na+ channel and ankyrinG accumulation at nodes of Ranvier without affecting myelination extent, demonstrating that NrCAM-neurofascin interactions are required for nodal Na+ channel clustering.","method":"Myelinating DRG-Schwann cell coculture, Nr-CAM-Fc fusion protein perturbation, immunofluorescence, co-precipitation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — functional perturbation with recombinant protein in defined coculture system, co-precipitation, multiple readouts","pmids":["11728309"],"is_preprint":false},{"year":2001,"finding":"Nr-CAM-deficient mice have functionally null Nr-CAM; cerebellar granule cells from these mice fail to extend neurites on contactin substrate in vitro, confirming contactin as an Nr-CAM ligand. Combined Nr-CAM/L1 double mutant mice exhibit severe cerebellar folial defects and reduced inner granule cell layer thickness, demonstrating overlapping functions of these related CAMs.","method":"Nr-CAM knockout mouse, neurite outgrowth assay on contactin substrate, histological analysis of double mutant cerebellum, antibody perturbation in culture","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mouse with defined in vitro and in vivo phenotypes; epistatic double mutant analysis","pmids":["11564762"],"is_preprint":false},{"year":2001,"finding":"Targeted ablation of NrCAM in mice causes formation of mature cataracts due to disorganization of lens fiber cells, accompanied by abnormalities in the cytoskeleton and connexin50-containing gap junctions. Ankyrin-B mutant mice display an indistinguishable lens fiber disorganization phenotype, providing genetic evidence that NrCAM and ankyrin-B interact to maintain lens fiber cell contacts.","method":"NrCAM knockout mouse, ankyrin-B mutant mouse, histology, immunostaining, electron microscopy, genetic epistasis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent genetic models (NrCAM KO and ankyrin-B KO) produce identical phenotype, establishing functional interaction; multiple analytical methods","pmids":["11449000"],"is_preprint":false},{"year":2002,"finding":"Nr-CAM is a direct transcriptional target gene of the beta-catenin/LEF-1 signaling pathway. LEF/TCF binding sites in the Nr-CAM promoter were required for activation by beta-catenin or plakoglobin. Retroviral transduction of Nr-CAM into NIH3T3 cells stimulated cell growth, motility, transformation, and tumor formation in nude mice. Dominant-negative LEF-1 decreased Nr-CAM expression; anti-Nr-CAM antibodies inhibited B16 melanoma motility.","method":"DNA microarray, promoter-reporter assay with LEF/TCF site mutation, retroviral transduction, cell growth/motility assays, nude mouse xenograft, dominant-negative LEF-1","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — promoter mutagenesis establishing direct transcriptional regulation, functional gain-of-function, and in vivo tumorigenesis; multiple orthogonal methods","pmids":["12183361"],"is_preprint":false},{"year":2003,"finding":"NrCAM (ankyrinG-binding protein) precedes Na+ channels at cluster sites adjacent to Schwann cell process tips during node of Ranvier formation. In NrCAM null mutants, both Na+ channel and ankyrinG sequestration at developing nodes are delayed. NrCAM acts locally at individual nodes (not globally on neuronal expression) and its action is linked to glial contact.","method":"NrCAM null mutant mouse, immunostaining during node development, quantitative analysis of Na+ channel/ankyrinG clustering timing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null with defined temporal phenotype, multiple molecular readouts, confirms and extends coculture findings","pmids":["14602817"],"is_preprint":false},{"year":2004,"finding":"NrCAM coupling to the retrograde actin flow requires both cytoplasmic tail interactions and cis-interactions via FNIII domains (deletion of both is needed to abolish retrograde movement). Additionally, NrCAM-actin coupling requires partitioning into lipid rafts, as cholesterol depletion by methyl-beta-cyclodextrin abolished retrograde movement. TAG-1 bead binding induced coalescence of lipid rafts (caveolin-1 recruitment) at adhesive contact sites.","method":"Optical tweezers, single particle tracking, deletion mutants of NrCAM, cholesterol depletion with methyl-beta-cyclodextrin, FRAP, immunofluorescence for caveolin-1","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biophysical methods (optical tweezers, SPT, FRAP) combined with mutagenesis and pharmacological perturbation in one rigorous study","pmids":["15254265"],"is_preprint":false},{"year":2005,"finding":"NrCAM undergoes metalloprotease-mediated ectodomain shedding. Conditioned medium and purified Nr-CAM-Fc fusion protein both enhanced cell motility, proliferation, and activated ERK and AKT signaling pathways. NrCAM was found in complex with alpha4beta1 integrins in melanoma cells. Stable expression of the ectodomain alone was sufficient to confer cell transformation and tumorigenesis in mice.","method":"Metalloprotease shedding detection, conditioned medium assays, co-immunoprecipitation with alpha4beta1 integrins, ERK/AKT phosphorylation assays, siRNA knockdown, nude mouse tumor assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP of NrCAM-integrin complex, biochemical signaling assays, loss-of-function (siRNA) and gain-of-function (ectodomain expression) with in vivo readout","pmids":["16357171"],"is_preprint":false},{"year":2006,"finding":"The cytoplasmic carboxy-terminus of NrCAM contains a PDZ-binding motif that specifically interacts with class I PDZ domains of SAP90/PSD95 and SAP97. This interaction is unique among L1 family members (L1, CHL1, Neurofascin do not bind these PDZ domains). In transfected COS-7 cells, NrCAM-mediated recruitment of SAP97 to the plasma membrane required the PDZ-binding motif. NrCAM and SAP97 colocalize in photoreceptor terminals.","method":"PDZ domain binding assay, transfection of COS-7 cells with PDZ-motif mutants, immunocytochemistry co-localization","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct interaction assay with mutagenesis confirming functional PDZ motif; single lab, multiple methods including specificity comparisons across L1 family","pmids":["16882004"],"is_preprint":false},{"year":2006,"finding":"Nr-CAM expressed on contralateral retinal ganglion cells (RGCs) is critical for guidance of late-born VTC RGCs at the optic chiasm. Blocking Nr-CAM function increases the ipsilateral projection size and reduces neurite outgrowth on chiasm cells in an age- and region-specific manner. EphB1/ephrin-B2-mediated repulsion and Nr-CAM-mediated attraction are distinct parallel molecular programs governing binocular visual pathway formation.","method":"Nr-CAM null mouse, anterograde axon tracing, in vitro neurite outgrowth on chiasm cell substrate, antibody blocking","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mouse with defined axon tracing phenotype, in vitro functional assay; distinct from EphB pathway by genetic analysis","pmids":["16701205"],"is_preprint":false},{"year":2010,"finding":"Initial clustering of Na+ channels at PNS heminodes requires glial NrCAM and gliomedin acting through their axonal receptor neurofascin 186 (NF186). This glial signal is distinct from a second paranodal junction-dependent mechanism. NrCAM and gliomedin cooperate to capture Na+ channels at heminodes before fusion into mature nodes.","method":"Gliomedin/NrCAM knockout mice, immunostaining during PNS development, electron microscopy","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mice with mechanistically defined two-step nodal assembly pathway; replicated by subsequent long-term maintenance paper","pmids":["20188654"],"is_preprint":false},{"year":2011,"finding":"NrCAM forms a molecular complex with neuropilin-2 (Npn-2) in brain and neural cells. Genetic deletion of NrCAM causes misprojection of thalamic axons caudally at the ventral telencephalon and striking mistargeting of motor and somatosensory thalamic axons to primary visual cortex. NrCAM is required for Sema3F-induced growth cone collapse in thalamic neuron cultures, consistent with a role in Sema3F-induced axon repulsion via the NrCAM-Npn-2 complex.","method":"NrCAM null mouse, anterograde axon tracing, co-immunoprecipitation of NrCAM-Npn-2 complex, growth cone collapse assay, visual evoked potentials","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of receptor complex, genetic null with in vivo axon tracing, in vitro functional assay; multiple orthogonal methods","pmids":["21273439"],"is_preprint":false},{"year":2012,"finding":"Sema6D and Nr-CAM are expressed on midline radial glia and Plexin-A1 on chiasm neurons; Plexin-A1 and Nr-CAM are also expressed on contralateral RGCs. Nr-CAM functions as a receptor for Sema6D. Sema6D in combination with Nr-CAM and Plexin-A1 converts Sema6D-mediated repulsion to growth promotion for contralateral RGCs. All three (Sema6D, Plexin-A1, NrCAM) are required for efficient RGC decussation.","method":"Knockout mouse analysis, in vitro growth assays, receptor identification experiments, genetic interaction analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockout analyses, functional conversion of repulsion to attraction, receptor identification for Sema6D; orthogonal in vitro and in vivo approaches","pmids":["22632726"],"is_preprint":false},{"year":2013,"finding":"NrCAM contributes to mediolateral retinocollicular axon targeting through regulation of RGC axon branch orientation. EphB2 tyrosine kinase (but not kinase-dead EphB2) phosphorylates NrCAM at a conserved tyrosine in the FIGQY ankyrin-binding motif, perturbing ankyrin recruitment in NrCAM-transfected HEK293 cells. In vivo, phospho-FIGQY NrCAM in SC is decreased in EphB1/3 null mice and increased in constitutively active EphB2 mice.","method":"NrCAM null mouse axon tracing, EphB kinase phosphorylation assay in HEK293 cells, kinase-dead mutant, EphB null mouse analysis, ankyrin recruitment assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct kinase assay with mutagenesis, in vivo genetic confirmation in multiple mouse models, ankyrin-binding functional consequence","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 the extracellular Ig1 domain. NrCAM deletion elevates spine density on apical dendrites and increases mEPSC frequency. Recombinant Sema3F-Fc induced spine retraction on wild-type but not NrCAM-null neurons; re-expression of NrCAM rescued the response. Trans heterozygous genetic interaction confirmed NrCAM and Sema3F pathways interact in vivo.","method":"NrCAM null mouse, co-immunoprecipitation, spine density quantification, electron microscopy, whole-cell electrophysiology, rescue experiments, trans heterozygous genetic interaction","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP of holoreceptor complex, KO phenotype, rescue, electrophysiology, genetic epistasis; multiple orthogonal methods in one rigorous study","pmids":["25143608"],"is_preprint":false},{"year":2014,"finding":"Long-term maintenance of Na+ channels at PNS nodes of Ranvier requires axoglial contact mediated by both gliomedin and NrCAM together. Mice lacking both molecules (but not either alone) show gradual loss of nodal Na+ channels and other axonal components, formation of binary nodes, dysregulation of nodal gap length, and neurological abnormalities. Node disintegration follows the reverse order of assembly: NF186 disappears first, then Na+ channels and ankyrinG, then βIV spectrin.","method":"Gliomedin/NrCAM double knockout mouse, immunostaining, electron microscopy, electrophysiology, behavioral analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — double knockout genetic analysis with ordered molecular disassembly, electrophysiology, EM; extends prior single-KO work","pmids":["24719088"],"is_preprint":false},{"year":2017,"finding":"NrCAM activates MAPK/Erk and PI3K/Akt signaling pathways via ectodomain shedding and binding to EGFR and α4β1 integrins. These pathways in turn upregulate NrCAM expression through the GSK3β/β-catenin axis, establishing positive feedback loops. NrCAM depletion inhibited thyroid cancer cell growth and invasiveness.","method":"NrCAM knockdown and overexpression in thyroid cancer cells, phosphorylation assays, co-immunoprecipitation, nude mouse xenograft, transgenic BrafV600E mouse","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, signaling assays, in vivo models; single lab but multiple cell and animal model approaches","pmids":["27732334"],"is_preprint":false},{"year":2019,"finding":"NrCAM functions as a substrate for ADAM10 metalloprotease cleavage. ADAM10 controls NrCAM surface levels and regulates neurite outgrowth in an NrCAM-dependent manner in vitro. However, ADAM10 cleavage of NrCAM (unlike APP) is not stimulated by the ADAM10 activator acitretin, suggesting substrate-selective ADAM10 activation is feasible and that NrCAM can serve as a biomarker of basal (non-stimulated) ADAM10 activity.","method":"ADAM10 activity assay, NrCAM surface level quantification, neurite outgrowth assay, human CSF proteomics from clinical trial","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct substrate identification with functional consequence (neurite outgrowth), selectivity demonstrated by comparison to APP, validated in human CSF proteomics","pmids":["30833305"],"is_preprint":false},{"year":2019,"finding":"NrCAM promotes clustering of the Sema3F holoreceptor complex by interfacing with Neuropilin-2 (Npn-2) and the PDZ scaffold protein SAP102. NrCAM-induced receptor clustering stimulates Rap-GAP activity of PlexinA3 (PlexA3) within the holoreceptor complex, which inhibits Rap1-GTPase and inactivates adhesive β1 integrins, mediating Sema3F-induced spine pruning during adolescence. Conditional inducible NrCAM deletion (Nex1Cre-ERT2:NrCAMflox/flox) showed NrCAM acts cell-autonomously in pyramidal neurons.","method":"Conditional inducible knockout mouse, molecular modeling, holoreceptor complex assembly assay, Rap-GAP activity assay, Rap1-GTPase assay, β1 integrin activity assay, spine density quantification","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO, enzymatic (Rap-GAP) assay, integrin activity measurement, receptor clustering; multiple orthogonal mechanistic approaches","pmids":["29415226"],"is_preprint":false},{"year":2019,"finding":"NrCAM mediates fasciculation of axon fibers in the stria terminalis, regulating amygdala-BNST connectivity. NrCAM null mice show pronounced defasciculation and misprojection of fibers in the stria terminalis and are impaired in context-dependent (but not cued) fear conditioning, linking NrCAM-mediated axon fasciculation to amygdalar-BNST circuit function.","method":"NrCAM null mouse, neurofilament immunohistochemistry of fiber tracts, contextual vs. cued fear conditioning behavioral testing","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null with defined anatomical and behavioral phenotypes; single lab with orthogonal morphological and behavioral readouts","pmids":["30766872"],"is_preprint":false},{"year":2018,"finding":"Neurocan (a chondroitin sulfate proteoglycan) inhibits Sema3F-induced spine elimination through binding to NrCAM. Cell binding and ELISA assays demonstrated association of Neurocan with NrCAM. Neurocan blocked Sema3F-induced morphological retraction in COS-7 cells mediated through NrCAM, Npn-2, and PlexinA3. Glycosaminoglycan chains of Neurocan (but not the C-terminal sushi domain) were required for this inhibition.","method":"Cell binding assay, ELISA, COS-7 cell morphology assay, cortical neuron culture spine assay, domain deletion analysis","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct binding assay, functional blocking in two cell systems, domain requirement established; single lab","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 variant) at the expense of Nrcam-10 in injured DRG. Antisense oligonucleotides (ASO) targeting exon 10 attenuated mechanical allodynia, thermal hyperalgesia, and cold allodynia in SNL and CCD models in both male and female mice.","method":"RNA sequencing, ASO treatment (DRG microinjection and intrathecal), behavioral pain assays (von Frey, thermal, cold plate)","journal":"The journal of pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific ASO intervention with defined splicing change, multiple pain behavioral readouts, two injury models; single lab","pmids":["31917219"],"is_preprint":false},{"year":2022,"finding":"NrCAM and Ankyrin B mediate perisomatic synaptic contact between CCK-basket cells (CCK-BCs) and pyramidal neurons (PNs) in mouse medial prefrontal cortex. NrCAM-null mice show significant decreases in CCK-BC (VGLUT3+ and VGAT+) synaptic puncta on PN soma but no decrease in PV-BC puncta or cell loss. Ankyrin B deletion specifically from PNs also reduces VGLUT3+ CCK-BC puncta, establishing that postsynaptic NrCAM-Ankyrin B interaction is required for CCK-BC synapse formation.","method":"NrCAM null mouse, conditional Ankyrin B deletion (Nex1Cre-ERT2:Ank2flox/flox), CCK-BC reporter mouse (Sncg-tdTomato), immunolabeling, confocal quantification","journal":"Current research in neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic models (NrCAM KO and conditional Ank2 KO) converging on same synaptic phenotype; single lab","pmids":["40276719"],"is_preprint":false},{"year":2022,"finding":"NrCAM activates the NF-κB signaling pathway by competitively binding to SUMO-1, reducing IκBα SUMOylation and increasing IκBα phosphorylation and degradation, thereby promoting NF-κB-dependent Th17 cell differentiation. NrCAM overexpression increased IL-21 via NF-κB (p65 binding to IL-21 promoter), and NF-κB inhibitor BAY11-7082 partially reversed NrCAM's effects.","method":"NrCAM overexpression and knockdown in CD4+ T cells, flow cytometry for Th17 markers, co-immunoprecipitation of NrCAM-SUMO-1, p-IκBα western blot, ChIP for p65 on IL-21 promoter, NF-κB inhibitor treatment","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP of NrCAM-SUMO-1 complex, ChIP, multiple signaling readouts; single lab, non-neural context but mechanistically informative","pmids":["39155774"],"is_preprint":false},{"year":2023,"finding":"In hepatocellular carcinoma (HCC), NrCAM promotes liver cancer stem cell (LCSC) migration, invasion, and metastasis by activating epithelial-mesenchymal transition (EMT) and matrix metalloproteinases (MMPs) through the MACF1-mediated β-catenin signaling pathway in LCSCs.","method":"MYC-driven LCSC organoids, NrCAM knockdown and overexpression, invasion/migration assays, in vivo tumor allografts (intra-hepatic and lung metastasis), scRNA-seq, MACF1/β-catenin pathway analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional studies with pathway identification; single lab, specific mechanistic pathway (MACF1/β-catenin)","pmids":["37993901"],"is_preprint":false},{"year":2023,"finding":"Rbfox1 (RNA-binding Fox1) regulates alternative splicing of NrCAM exon 10 in DRG after spinal nerve ligation. Downregulation of Rbfox1 following nerve injury amplifies exon 10 insertion (L-Nrcam increase, S-Nrcam decrease). Restoring Rbfox1 mitigates nociceptive hypersensitivity; mimicking Rbfox1 downregulation generates neuropathic pain symptoms.","method":"Transcriptome profiling (RNA-seq), bioinformatic splicing analysis, Rbfox1 overexpression/knockdown in DRG, splicing isoform quantification, behavioral pain assays","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identification of splicing regulator with functional rescue/phenocopy; extends prior Nrcam splicing/pain work; single lab","pmids":["38241164"],"is_preprint":false},{"year":2025,"finding":"The NRCAM proteoform with microexons 5 and 19 skipped (Δex5Δex19 NRCAM) is uniformly expressed in pediatric high-grade gliomas but not normal brain. This specific splice variant (not full-length NrCAM) is essential for pHGG cell migration, invasion in vitro, and tumor growth in vivo. A monoclonal antibody selective for Δex5Δex19 NRCAM enables T-cell-mediated killing of pHGG cells via an FcRI-based universal immune receptor.","method":"Bulk and single-nuclei short- and long-read RNA-seq, loss-of-function assays (migration/invasion in vitro), in vivo tumor growth, monoclonal antibody development, T-cell killing assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — RNA-seq identification, loss-of-function in vitro and in vivo, antibody selectivity validation; multiple orthogonal approaches in one study","pmids":["40782352"],"is_preprint":false}],"current_model":"NrCAM is a transmembrane cell adhesion molecule of the L1/Ig superfamily whose cytoplasmic domain links to ankyrin (via the FIGQY motif) and the actin cytoskeleton (via lipid raft-mediated coupling and FNIII cis-interactions), while its extracellular Ig and FNIII domains mediate homophilic binding and heterophilic interactions with axonin-1/TAG-1, contactin/F3, neurofascin, F11, RPTPβ, Sema6D, and integrins to regulate axon guidance, node of Ranvier Na⁺ channel clustering, dendritic spine pruning (as part of the Sema3F/Npn-2/PlexA3 holoreceptor complex that activates Rap-GAP/Rap1 to inactivate β1 integrins), perisomatic CCK-basket cell synapse formation (via Ankyrin B), and—through ectodomain shedding—oncogenic ERK/AKT activation; NrCAM expression is transcriptionally driven by the β-catenin/LEF-1 pathway, post-translationally regulated by EphB2 phosphorylation at FIGQY and ADAM10 cleavage, and functionally modulated by alternative splicing of exon 10 (regulated by Rbfox1 in DRG) which controls neuropathic pain."},"narrative":{"mechanistic_narrative":"NRCAM (Nr-CAM/Bravo) is a neural transmembrane glycoprotein of the L1/Ig adhesion superfamily, built from six Ig-like domains, five fibronectin type III repeats, a transmembrane segment, and a short ankyrin-binding cytoplasmic tail, that organizes axon guidance, node of Ranvier assembly, and synapse formation through homophilic and heterophilic adhesion [PMID:2045418, PMID:1527169]. Its extracellular domains engage a wide partner repertoire—contactin/F3, axonin-1/TAG-1, neurofascin, F11, and RPTPβ—to drive neurite outgrowth, neuron-glia contact, and directional pathfinding of commissural and retinal ganglion cell axons at the midline and optic chiasm [PMID:8274278, PMID:7541632, PMID:7490283, PMID:9049255, PMID:16701205], while its cytoplasmic FIGQY motif binds ankyrins to couple the membrane to the cytoskeleton, a linkage further reinforced by lipid-raft partitioning and FNIII cis-interactions that tether NrCAM to retrograde actin flow [PMID:7961622, PMID:10462518, PMID:15254265]. At nodes of Ranvier and axon initial segments, glial NrCAM acting with gliomedin and neurofascin-186 captures and stabilizes voltage-gated Na⁺ channels and ankyrinG, and is required for both initial clustering and long-term nodal maintenance [PMID:8947556, PMID:11728309, PMID:14602817, PMID:20188654, PMID:24719088]. Postsynaptically, NrCAM nucleates the Sema3F holoreceptor (with Neuropilin-2 and PlexinA3) and, via SAP102, activates PlexinA3 Rap-GAP activity to inactivate β1 integrins and drive dendritic spine pruning, and through ankyrin B it builds perisomatic CCK-basket cell synapses [PMID:21273439, PMID:25143608, PMID:29415226, PMID:40276719]. NrCAM activity is tuned by EphB2 phosphorylation of the FIGQY motif, by ADAM10/metalloprotease ectodomain shedding that liberates a fragment activating ERK/AKT signaling, by β-catenin/LEF-1 transcriptional control, and by Rbfox1-regulated exon 10 splicing that governs neuropathic pain [PMID:12183361, PMID:16357171, PMID:24023801, PMID:30833305, PMID:31917219, PMID:38241164]. In cancer, NrCAM ectodomain shedding and integrin/EGFR engagement drive ERK/AKT and β-catenin signaling to promote transformation, invasion, and metastasis, and a tumor-specific Δex5Δex19 splice proteoform is essential for pediatric high-grade glioma growth [PMID:12183361, PMID:16357171, PMID:27732334, PMID:37993901, PMID:40782352].","teleology":[{"year":1991,"claim":"Establishing NrCAM as a discrete molecular entity defined its domain architecture and placed it as a candidate neural adhesion receptor.","evidence":"cDNA cloning, protein purification, and N-terminal sequencing of the 145-kDa neural glycoprotein","pmids":["2045418"],"confidence":"High","gaps":["Function inferred from structure only","No binding partners yet identified"]},{"year":1992,"claim":"Demonstrating that NrCAM mediates both homophilic and heterophilic adhesion, and is post-translationally cleaved into an alpha/beta heterodimer, defined it functionally as an adhesion molecule.","evidence":"Cell aggregation and substrate binding assays with recombinant FGTNr, L-cell transfection, plus SDS-PAGE/sequence analysis of the cleaved chains","pmids":["1527169","1512296"],"confidence":"High","gaps":["Specific heterophilic ligands unidentified","Functional role of cleavage not established"]},{"year":1993,"claim":"Identifying F11/contactin as a direct heterophilic ligand connected NrCAM adhesion to a concrete neurite-outgrowth output and mapped the binding interface.","evidence":"Neurite outgrowth on immobilized F11, antibody blocking, COS-cell binding, and F11 deletion mutants","pmids":["8274278"],"confidence":"High","gaps":["Downstream signaling from the F11-NrCAM interaction unresolved"]},{"year":1994,"claim":"Showing the cytoplasmic domain binds ankyrins established the membrane-cytoskeleton linkage that underlies NrCAM clustering and stabilization.","evidence":"Biochemical co-association and protein quantification from brain membrane fractions","pmids":["7961622"],"confidence":"High","gaps":["Sequence determinant (FIGQY) not yet defined","Functional consequence in vivo untested"]},{"year":1995,"claim":"Demonstrating that floor-plate NrCAM engages growth-cone axonin-1 to direct commissural midline crossing gave NrCAM a defined in vivo guidance function.","evidence":"In vivo antibody perturbation in chick spinal cord and histological axon trajectory analysis, plus axonin-1/NrCAM binding on peripheral glia","pmids":["7541632","7490283"],"confidence":"High","gaps":["Signal transduction converting adhesion to guidance unknown","Receptor-side cytoplasmic mechanism undefined"]},{"year":1996,"claim":"Co-localizing NrCAM with neurofascin, ankyrinG, and Na+ channels at nodes of Ranvier, and demonstrating direct NrCAM-neurofascin binding, positioned NrCAM at the heart of nodal assembly.","evidence":"Isoform-specific antibody immunofluorescence, COS-cell binding, immunoprecipitation, and reciprocal neurite outgrowth assays","pmids":["8947556","8922386"],"confidence":"High","gaps":["Causal requirement for Na+ channel clustering not yet tested","Glial vs axonal contributions unseparated"]},{"year":1997,"claim":"Showing RPTPβ binds a contactin-NrCAM complex linked NrCAM adhesion to a phosphatase-coupled neuronal differentiation signal.","evidence":"Co-immunoprecipitation, antibody-blocked neurite outgrowth, and transfected-cell differentiation co-culture","pmids":["9049255"],"confidence":"High","gaps":["Phosphatase substrates downstream of the complex unidentified"]},{"year":1999,"claim":"Defining NrCAM as a substrate ligand for axonin-1 and F3 receptors, and coupling F3-induced clustering to retrograde actin flow, mechanistically connected adhesion to growth-cone motility.","evidence":"Recombinant Fc fusion substrate assays, in ovo injection, microsphere tracking, and cytochalasin B disruption of retrograde movement","pmids":["10328925","10462518"],"confidence":"High","gaps":["Molecular bridge between cytoplasmic tail and actin not defined","Lipid-raft requirement not yet established"]},{"year":2001,"claim":"Genetic null mice and Fc-perturbation cocultures established that NrCAM is functionally required in vivo for cerebellar neurite outgrowth, nodal Na+ channel clustering, and (with ankyrin-B) lens fiber organization.","evidence":"NrCAM knockout and ankyrin-B mutant mice, contactin-substrate neurite assays, myelinating DRG-Schwann cocultures, histology and EM","pmids":["11564762","11449000","11728309"],"confidence":"High","gaps":["Redundancy with L1-family members complicates single-KO interpretation","Temporal sequence of nodal assembly not yet resolved"]},{"year":2002,"claim":"Identifying NrCAM as a direct β-catenin/LEF-1 transcriptional target and a transforming gene shifted it from a developmental adhesion molecule to an oncogenic effector.","evidence":"Microarray, promoter-reporter assays with LEF/TCF site mutation, retroviral transduction, motility/growth assays, and nude-mouse xenografts","pmids":["12183361"],"confidence":"High","gaps":["Mechanism by which surface NrCAM promotes motility unresolved at this stage"]},{"year":2003,"claim":"Temporal analysis in null mice showed NrCAM precedes and locally captures Na+ channels at developing nodes, defining it as an early glial-contact-dependent nodal organizer.","evidence":"NrCAM null mouse with quantitative developmental immunostaining of Na+ channel/ankyrinG timing","pmids":["14602817"],"confidence":"High","gaps":["Identity of cooperating glial ligand not yet defined"]},{"year":2004,"claim":"Biophysical dissection showed NrCAM-actin coupling requires both cytoplasmic and FNIII cis-interactions plus lipid-raft partitioning, refining the mechanics of adhesion-driven traction.","evidence":"Optical tweezers, single-particle tracking, FRAP, NrCAM deletion mutants, and cholesterol depletion","pmids":["15254265"],"confidence":"High","gaps":["Specific raft-resident adaptors not identified"]},{"year":2005,"claim":"Demonstrating metalloprotease ectodomain shedding that activates ERK/AKT via integrin association established a soluble-fragment signaling mechanism for NrCAM oncogenicity.","evidence":"Shedding detection, conditioned-medium assays, co-IP with α4β1 integrins, ERK/AKT phosphorylation, siRNA, and ectodomain-expression tumor assays","pmids":["16357171"],"confidence":"High","gaps":["Specific sheddase identity not pinned down at this stage","Receptor for the shed ectodomain incompletely defined"]},{"year":2006,"claim":"Identifying a unique PDZ-binding motif binding SAP90/PSD95 and SAP97, and a role in retinal chiasm guidance, extended NrCAM's scaffold interactions and CNS guidance functions.","evidence":"PDZ binding and mutagenesis in COS-7 cells, co-localization, NrCAM null axon tracing, and chiasm-cell neurite assays","pmids":["16882004","16701205"],"confidence":"High","gaps":["Functional consequence of PDZ scaffolding at synapses untested here","Relationship to EphB guidance program parallel but mechanistically separate"]},{"year":2011,"claim":"Discovering an NrCAM-Neuropilin-2 complex required for Sema3F-induced growth cone collapse assigned NrCAM a co-receptor role in semaphorin-mediated axon repulsion and thalamocortical targeting.","evidence":"NrCAM null mouse axon tracing, co-IP of NrCAM-Npn-2, growth cone collapse assays, and visual evoked potentials","pmids":["21273439"],"confidence":"High","gaps":["Signaling output of the complex not yet defined","Plexin involvement not yet incorporated"]},{"year":2012,"claim":"Showing NrCAM acts as a Sema6D receptor with Plexin-A1 that converts repulsion to growth promotion clarified how a single ligand can be reinterpreted to drive RGC decussation.","evidence":"Knockout mouse analyses, in vitro growth assays, and receptor identification with genetic interaction tests","pmids":["22632726"],"confidence":"High","gaps":["Structural basis of the repulsion-to-attraction switch unresolved"]},{"year":2014,"claim":"Defining NrCAM as a component of the Sema3F holoreceptor that restricts dendritic spine density established its postsynaptic role in spine pruning.","evidence":"NrCAM null mouse, co-IP of Npn-2/PlexA3, spine quantification, EM, electrophysiology, and Sema3F-Fc rescue","pmids":["25143608"],"confidence":"High","gaps":["Intracellular effector linking the complex to spine retraction not yet identified"]},{"year":2013,"claim":"Demonstrating EphB2 kinase phosphorylates the NrCAM FIGQY motif to perturb ankyrin recruitment defined a switch coupling Eph signaling to NrCAM-cytoskeleton uncoupling in axon targeting.","evidence":"EphB kinase and kinase-dead assays in HEK293, ankyrin-recruitment assays, NrCAM null axon tracing, and EphB null/constitutively active mouse analysis","pmids":["24023801"],"confidence":"High","gaps":["In vivo dynamics of phospho-FIGQY regulation incompletely mapped"]},{"year":2019,"claim":"Mechanistic dissection showed NrCAM clusters the Sema3F holoreceptor via SAP102 to activate PlexinA3 Rap-GAP, inactivating β1 integrins for spine pruning, and identified ADAM10 as the sheddase controlling surface NrCAM.","evidence":"Conditional inducible NrCAM knockout, Rap-GAP/Rap1-GTPase and β1-integrin activity assays, modeling, ADAM10 activity assays, neurite outgrowth, and human CSF proteomics","pmids":["29415226","30833305"],"confidence":"High","gaps":["Quantitative balance of adhesion vs pruning signaling unresolved","ADAM10-NrCAM cleavage site not mapped"]},{"year":2019,"claim":"Linking NrCAM-mediated stria terminalis fasciculation to contextual fear behavior connected its axon-bundling role to circuit-level function.","evidence":"NrCAM null mouse, neurofilament immunohistochemistry, and contextual vs cued fear conditioning","pmids":["30766872"],"confidence":"Medium","gaps":["Molecular mechanism of fasciculation in this tract not dissected","Single lab; behavioral causality indirect"]},{"year":2018,"claim":"Identifying Neurocan as an NrCAM-binding inhibitor of Sema3F-induced spine elimination introduced an extracellular brake on the pruning pathway.","evidence":"Cell binding/ELISA, COS-7 and cortical neuron morphology assays, and Neurocan domain deletions","pmids":["30356641"],"confidence":"Medium","gaps":["Stoichiometry and competition with Sema3F not quantified","Single lab"]},{"year":2020,"claim":"Showing injury-induced exon 10 inclusion drives neuropathic pain, and that Rbfox1 governs this splicing, established a splice-isoform mechanism amenable to ASO intervention.","evidence":"RNA-seq, ASO targeting exon 10, Rbfox1 overexpression/knockdown in DRG, and behavioral pain assays in two injury models","pmids":["31917219","38241164"],"confidence":"Medium","gaps":["How the +10 isoform alters NrCAM adhesion/signaling in nociceptors undefined","Single-lab studies"]},{"year":2022,"claim":"Defining a postsynaptic NrCAM-ankyrin B requirement for CCK-basket cell perisomatic synapses extended NrCAM's role to inhibitory synapse specificity.","evidence":"NrCAM null and conditional Ank2 knockout mice with CCK-BC reporter and confocal puncta quantification","pmids":["40276719"],"confidence":"Medium","gaps":["Trans-synaptic partner on CCK-BC axons not identified","Single lab"]},{"year":2022,"claim":"Demonstrating NrCAM activates NF-κB by competing for SUMO-1 to destabilize IκBα, promoting Th17 differentiation, extended NrCAM signaling beyond the nervous system.","evidence":"NrCAM overexpression/knockdown in CD4+ T cells, co-IP with SUMO-1, p-IκBα western, p65 ChIP on IL-21 promoter, and NF-κB inhibitor","pmids":["39155774"],"confidence":"Medium","gaps":["How a transmembrane CAM accesses cytoplasmic SUMO-1 mechanistically unclear","Single lab, non-neural context"]},{"year":2023,"claim":"Identifying NrCAM-driven MACF1/β-catenin signaling in hepatocellular carcinoma stem cells reinforced its pro-metastatic role via EMT and MMP induction.","evidence":"MYC-driven LCSC organoids, knockdown/overexpression, invasion assays, allografts, scRNA-seq, and pathway analysis","pmids":["37993901"],"confidence":"Medium","gaps":["Direct physical link between NrCAM and MACF1 not established","Single lab"]},{"year":2025,"claim":"Discovering a tumor-restricted Δex5Δex19 NRCAM proteoform essential for pediatric high-grade glioma and targetable by a selective antibody established splice-variant-specific NrCAM as a therapeutic target.","evidence":"Short- and long-read RNA-seq, loss-of-function migration/invasion and in vivo growth assays, and a variant-selective monoclonal antibody enabling T-cell killing","pmids":["40782352"],"confidence":"High","gaps":["Mechanism by which microexon skipping confers tumor dependence unresolved","Functional difference between Δex5Δex19 and full-length signaling undefined"]},{"year":null,"claim":"The structural and signaling rules that determine whether NrCAM acts as an adhesive stabilizer versus a repulsion/pruning effector, and how its many splice isoforms reprogram these outputs across tissues, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of NrCAM bound to its ligands","Isoform-specific binding and signaling outputs not systematically compared","Mechanism converting adhesion to growth-cone steering still inferential"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,3,6,8,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[23,24,26,30]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,11,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[20,30]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,7,20]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[11,18]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,12,21,23,24,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,19,28,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,19,28,36,38]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,13,17,22,27]}],"complexes":["Sema3F holoreceptor (NrCAM/Neuropilin-2/PlexinA3)","node of Ranvier Na+ channel complex (with neurofascin/ankyrinG)","contactin/NrCAM-RPTPβ complex"],"partners":["CNTN1","CNTN2","NFASC","ANK2","NRP2","PLXNA3","PTPRZ1","DLG1"],"other_free_text":[]}},"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":286,"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 its relationship to subgroups of neural cell adhesion molecules.","date":"1991","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2045418","citation_count":179,"is_preprint":false},{"pmid":"20188654","id":"PMC_20188654","title":"A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier.","date":"2010","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/20188654","citation_count":165,"is_preprint":false},{"pmid":"9049255","id":"PMC_9049255","title":"Induction of neurite outgrowth through contactin and Nr-CAM by extracellular regions of glial receptor tyrosine phosphatase beta.","date":"1997","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9049255","citation_count":153,"is_preprint":false},{"pmid":"12183361","id":"PMC_12183361","title":"Nr-CAM is a target gene of the beta-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis.","date":"2002","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/12183361","citation_count":151,"is_preprint":false},{"pmid":"11866539","id":"PMC_11866539","title":"Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM.","date":"2002","source":"Microvascular research","url":"https://pubmed.ncbi.nlm.nih.gov/11866539","citation_count":138,"is_preprint":false},{"pmid":"22182708","id":"PMC_22182708","title":"The role of NrCAM in neural development and disorders--beyond a simple glue in the brain.","date":"2011","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/22182708","citation_count":113,"is_preprint":false},{"pmid":"8274278","id":"PMC_8274278","title":"Induction of axonal growth by heterophilic interactions between the cell surface recognition proteins F11 and 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activates the NF-κB signalling pathway by competitively binding to SUMO-1 and promotes Th17 cell differentiation in Graves' disease.","date":"2024","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39155774","citation_count":2,"is_preprint":false},{"pmid":"37035994","id":"PMC_37035994","title":"Cost-effectiveness analysis of once-daily insulin glargine 300 U/mL versus insulin degludec 100 U/mL using the BRAVO diabetes model.","date":"2023","source":"Diabetic medicine : a journal of the British Diabetic Association","url":"https://pubmed.ncbi.nlm.nih.gov/37035994","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50383,"output_tokens":10935,"usd":0.157587,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21849,"output_tokens":7509,"usd":0.148485,"stage2_stop_reason":"end_turn"},"total_usd":0.306072,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"Nr-CAM (NrCAM) was identified as a novel neural glycoprotein with a structure comprising six Ig-like domains, five fibronectin type III repeats, a transmembrane domain, and a short cytoplasmic domain, encoded by a single gene with alternatively spliced mRNAs. Purified protein (Mr 145,000) was confirmed by N-terminal sequencing matching the cDNA-predicted sequence.\",\n      \"method\": \"cDNA cloning, protein purification by lentil lectin affinity chromatography/FPLC, N-terminal sequencing, Northern and Southern blotting\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full-length cDNA sequencing, protein purification with biochemical verification; foundational structural characterization replicated by subsequent studies\",\n      \"pmids\": [\"2045418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"NrCAM (Bravo) mediates both homophilic (divalent cation-independent) and heterophilic (divalent cation-dependent) cell adhesion. Homophilic binding was demonstrated between transfected L cells and between cells and recombinant FGTNr (Ig domains 1-6 + first FNIII repeat fusion protein). Heterophilic binding occurred between NrCAM-transfected and untransfected L cells and between FGTNr and fibroblasts.\",\n      \"method\": \"Cell aggregation assay, substrate binding assay, Covasphere aggregation assay, recombinant fusion protein (FGTNr) inhibition, L-cell transfection\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro binding assays with recombinant proteins, transfected cells, and inhibitory reagents; replicated across systems\",\n      \"pmids\": [\"1527169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Bravo/NrCAM has a heterodimer structure composed of an alpha chain (Mr 140/130 kD) and a beta chain (60-80 kD) generated by cleavage of an intact polypeptide at a conserved Ser-Arg/Lys-Arg site, analogous to L1 and Ng-CAM. The molecule contains alternatively spliced sequences encoding both extra- and intracellular stretches.\",\n      \"method\": \"cDNA cloning, SDS-PAGE, sequence analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization with cDNA and protein analysis, single lab but consistent with parallel L1/NgCAM findings\",\n      \"pmids\": [\"1512296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Neurite extension of tectal cells on immobilized F11 (contactin) is mediated by NrCAM/Bravo on the axonal surface. Direct heterophilic binding between F11 and NrCAM/Bravo was demonstrated, and the interaction was mapped to the second or third Ig-like domain of F11 using domain-specific monoclonal antibodies and deletion mutant proteins expressed on COS cells.\",\n      \"method\": \"Neurite outgrowth assay, antibody blocking, COS cell binding assay, deletion mutants\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — neurite outgrowth functional assay combined with direct binding and domain mapping; multiple orthogonal approaches\",\n      \"pmids\": [\"8274278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The cytoplasmic domains of NrCAM (along with neurofascin, L1, NgCAM, and neuroglian) directly associate with ankyrins. NrCAM and neurofascin together comprise over 0.5% of total membrane protein in adult brain tissue, indicating this ankyrin linkage is a major membrane-cytoskeletal connection.\",\n      \"method\": \"Biochemical co-association assay, protein quantification from brain membrane fractions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical demonstration of ankyrin binding via cytoplasmic domain; replicated independently by node of Ranvier localization studies\",\n      \"pmids\": [\"7961622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In vivo perturbation experiments in chick showed that the interaction between axonin-1 on commissural growth cones and Nr-CAM on floor plate cells is required for accurate midline pathfinding. When axonin-1 or Nr-CAM interactions were perturbed (by antibody injection), many commissural axons failed to cross the midline and turned along the ipsilateral floor plate border instead.\",\n      \"method\": \"In vivo antibody perturbation in chick embryo spinal cord, histological analysis of axon trajectories\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct in vivo loss-of-function with specific phenotypic readout; foundational guidance study independently replicated\",\n      \"pmids\": [\"7541632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Axonin-1 binds directly to NrCAM on peripheral glial cells, mediating neuron-glia contacts. Fluorescent microspheres conjugated with axonin-1 bound to glial cells via NrCAM (identified by antibody blockage). Anti-axonin-1 and anti-NrCAM antibodies both perturbed neurite-glia contact formation in dissociated DRG cultures, implicating this interaction in early axon ensheathment.\",\n      \"method\": \"Microsphere binding assay, antibody blocking, purified protein binding assay, dissociated DRG neuron-glia culture perturbation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal binding and functional assays; direct interaction confirmed with purified proteins\",\n      \"pmids\": [\"7490283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NrCAM and a specific isoform of neurofascin (mucin+/third FNIII domain-) are colocalized with ankyrinG and voltage-dependent sodium channels at nodes of Ranvier and axon initial segments. NrCAM was identified by screening a rat brain cDNA expression library with anti-neurofascin antibody; it shares >70% cytoplasmic domain identity with neurofascin.\",\n      \"method\": \"cDNA library screening, isoform-specific antibody generation, immunofluorescence co-localization, cDNA sequencing\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with isoform-specific antibodies; replicated by multiple independent groups at nodes of Ranvier\",\n      \"pmids\": [\"8947556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Neurofascin promotes neurite extension from tectal cells by heterophilic interaction with NrCAM on axonal surfaces. Conversely, when NrCAM is the substrate, it induces neurite extension through F11 (not neurofascin) as the axonal receptor. Direct binding between neurofascin and NrCAM was demonstrated by transfected COS7 cell binding and immunoprecipitation, and mapped to the Ig domains of neurofascin. Alternative splicing of neurofascin modulates this binding.\",\n      \"method\": \"Neurite outgrowth assay on immobilized substrates, antibody blocking, COS7 cell transfection binding assay, immunoprecipitation, deletion mapping\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding assays, immunoprecipitation, domain mapping, functional neurite assays in one study\",\n      \"pmids\": [\"8922386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The extracellular region of glial receptor protein tyrosine phosphatase beta (RPTPbeta) binds to a complex of contactin and NrCAM on neurons. Neurite outgrowth induced by betaCFS (RPTPbeta fusion) was inhibited by antibodies against both NrCAM and contactin, and contactin/NrCAM co-immunoprecipitated with betaCFS. NIH-3T3 cells expressing betaCFS on their surfaces induced neuronal differentiation.\",\n      \"method\": \"Antibody blocking of neurite outgrowth, co-immunoprecipitation, recombinant fusion proteins, transfected cell co-culture assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP of complex, functional blocking, and cell-based differentiation assay in one study; multiple orthogonal approaches\",\n      \"pmids\": [\"9049255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NrCAM functions as a substrate ligand for neurite outgrowth from dorsal root ganglion (DRG) and sympathetic ganglion neurons via axonin-1 as the neuronal receptor. A recombinant Nr-CAM-Fc fusion protein (containing all 6 Ig domains and first 2 FNIII repeats) promoted neurite outgrowth from peripheral but not central neurons; anti-axonin-1 antibodies inhibited this outgrowth. In ovo injection of Nr-Fc produced commissural axon guidance errors similar to anti-axonin-1 treatment.\",\n      \"method\": \"Recombinant Fc fusion protein substrate assay, antibody blocking of neurite outgrowth, in ovo injection, immunostaining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro functional assay with defined recombinant protein plus in vivo confirmation; multiple approaches\",\n      \"pmids\": [\"10328925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NrCAM is the functional receptor on cerebellar granule cells for the neuronal adhesion glycoprotein F3 (contactin). F3Fc-conjugated microspheres bound growth cones via NrCAM (not L1). These beads moved retrogradely at 5.7 µm/min (actin retrograde flow velocity); cytochalasin B (actin disruptor) abolished this movement. NrCAM clustering (induced by cross-linked F3Fc) was required for retrograde mobility.\",\n      \"method\": \"Microsphere binding assay, time-lapse video microscopy, cytochalasin B treatment, single particle tracking\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding identification, live-cell imaging, pharmacological perturbation, mechanistic coupling to actin cytoskeleton demonstrated\",\n      \"pmids\": [\"10462518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Axonin-1 interaction with floor-plate NrCAM mediates commissural axon guidance (directionality) without promoting axon elongation. In stripe assays, commissural axons preferred NrCAM+NgCAM stripes; anti-axonin-1 abolished this preference without reducing neurite length. In vivo, axonin-1/NrCAM perturbation selectively caused guidance failure, not elongation defects.\",\n      \"method\": \"In vitro stripe assay, antibody blocking, in vivo perturbation with phenotypic measurement of guidance vs. elongation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection of guidance vs. elongation using orthogonal in vitro and in vivo approaches; clear functional discrimination\",\n      \"pmids\": [\"10811834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nr-CAM interacts with Nr-CAM-Fc fusion protein and with neurofascin on axonal surfaces to cluster neurofascin and co-precipitate it. Treatment of myelinating DRG-Schwann cell cocultures with Nr-CAM-Fc fusion protein specifically inhibited Na+ channel and ankyrinG accumulation at nodes of Ranvier without affecting myelination extent, demonstrating that NrCAM-neurofascin interactions are required for nodal Na+ channel clustering.\",\n      \"method\": \"Myelinating DRG-Schwann cell coculture, Nr-CAM-Fc fusion protein perturbation, immunofluorescence, co-precipitation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — functional perturbation with recombinant protein in defined coculture system, co-precipitation, multiple readouts\",\n      \"pmids\": [\"11728309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nr-CAM-deficient mice have functionally null Nr-CAM; cerebellar granule cells from these mice fail to extend neurites on contactin substrate in vitro, confirming contactin as an Nr-CAM ligand. Combined Nr-CAM/L1 double mutant mice exhibit severe cerebellar folial defects and reduced inner granule cell layer thickness, demonstrating overlapping functions of these related CAMs.\",\n      \"method\": \"Nr-CAM knockout mouse, neurite outgrowth assay on contactin substrate, histological analysis of double mutant cerebellum, antibody perturbation in culture\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mouse with defined in vitro and in vivo phenotypes; epistatic double mutant analysis\",\n      \"pmids\": [\"11564762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Targeted ablation of NrCAM in mice causes formation of mature cataracts due to disorganization of lens fiber cells, accompanied by abnormalities in the cytoskeleton and connexin50-containing gap junctions. Ankyrin-B mutant mice display an indistinguishable lens fiber disorganization phenotype, providing genetic evidence that NrCAM and ankyrin-B interact to maintain lens fiber cell contacts.\",\n      \"method\": \"NrCAM knockout mouse, ankyrin-B mutant mouse, histology, immunostaining, electron microscopy, genetic epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent genetic models (NrCAM KO and ankyrin-B KO) produce identical phenotype, establishing functional interaction; multiple analytical methods\",\n      \"pmids\": [\"11449000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Nr-CAM is a direct transcriptional target gene of the beta-catenin/LEF-1 signaling pathway. LEF/TCF binding sites in the Nr-CAM promoter were required for activation by beta-catenin or plakoglobin. Retroviral transduction of Nr-CAM into NIH3T3 cells stimulated cell growth, motility, transformation, and tumor formation in nude mice. Dominant-negative LEF-1 decreased Nr-CAM expression; anti-Nr-CAM antibodies inhibited B16 melanoma motility.\",\n      \"method\": \"DNA microarray, promoter-reporter assay with LEF/TCF site mutation, retroviral transduction, cell growth/motility assays, nude mouse xenograft, dominant-negative LEF-1\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — promoter mutagenesis establishing direct transcriptional regulation, functional gain-of-function, and in vivo tumorigenesis; multiple orthogonal methods\",\n      \"pmids\": [\"12183361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NrCAM (ankyrinG-binding protein) precedes Na+ channels at cluster sites adjacent to Schwann cell process tips during node of Ranvier formation. In NrCAM null mutants, both Na+ channel and ankyrinG sequestration at developing nodes are delayed. NrCAM acts locally at individual nodes (not globally on neuronal expression) and its action is linked to glial contact.\",\n      \"method\": \"NrCAM null mutant mouse, immunostaining during node development, quantitative analysis of Na+ channel/ankyrinG clustering timing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null with defined temporal phenotype, multiple molecular readouts, confirms and extends coculture findings\",\n      \"pmids\": [\"14602817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NrCAM coupling to the retrograde actin flow requires both cytoplasmic tail interactions and cis-interactions via FNIII domains (deletion of both is needed to abolish retrograde movement). Additionally, NrCAM-actin coupling requires partitioning into lipid rafts, as cholesterol depletion by methyl-beta-cyclodextrin abolished retrograde movement. TAG-1 bead binding induced coalescence of lipid rafts (caveolin-1 recruitment) at adhesive contact sites.\",\n      \"method\": \"Optical tweezers, single particle tracking, deletion mutants of NrCAM, cholesterol depletion with methyl-beta-cyclodextrin, FRAP, immunofluorescence for caveolin-1\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biophysical methods (optical tweezers, SPT, FRAP) combined with mutagenesis and pharmacological perturbation in one rigorous study\",\n      \"pmids\": [\"15254265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NrCAM undergoes metalloprotease-mediated ectodomain shedding. Conditioned medium and purified Nr-CAM-Fc fusion protein both enhanced cell motility, proliferation, and activated ERK and AKT signaling pathways. NrCAM was found in complex with alpha4beta1 integrins in melanoma cells. Stable expression of the ectodomain alone was sufficient to confer cell transformation and tumorigenesis in mice.\",\n      \"method\": \"Metalloprotease shedding detection, conditioned medium assays, co-immunoprecipitation with alpha4beta1 integrins, ERK/AKT phosphorylation assays, siRNA knockdown, nude mouse tumor assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP of NrCAM-integrin complex, biochemical signaling assays, loss-of-function (siRNA) and gain-of-function (ectodomain expression) with in vivo readout\",\n      \"pmids\": [\"16357171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The cytoplasmic carboxy-terminus of NrCAM contains a PDZ-binding motif that specifically interacts with class I PDZ domains of SAP90/PSD95 and SAP97. This interaction is unique among L1 family members (L1, CHL1, Neurofascin do not bind these PDZ domains). In transfected COS-7 cells, NrCAM-mediated recruitment of SAP97 to the plasma membrane required the PDZ-binding motif. NrCAM and SAP97 colocalize in photoreceptor terminals.\",\n      \"method\": \"PDZ domain binding assay, transfection of COS-7 cells with PDZ-motif mutants, immunocytochemistry co-localization\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct interaction assay with mutagenesis confirming functional PDZ motif; single lab, multiple methods including specificity comparisons across L1 family\",\n      \"pmids\": [\"16882004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nr-CAM expressed on contralateral retinal ganglion cells (RGCs) is critical for guidance of late-born VTC RGCs at the optic chiasm. Blocking Nr-CAM function increases the ipsilateral projection size and reduces neurite outgrowth on chiasm cells in an age- and region-specific manner. EphB1/ephrin-B2-mediated repulsion and Nr-CAM-mediated attraction are distinct parallel molecular programs governing binocular visual pathway formation.\",\n      \"method\": \"Nr-CAM null mouse, anterograde axon tracing, in vitro neurite outgrowth on chiasm cell substrate, antibody blocking\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mouse with defined axon tracing phenotype, in vitro functional assay; distinct from EphB pathway by genetic analysis\",\n      \"pmids\": [\"16701205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Initial clustering of Na+ channels at PNS heminodes requires glial NrCAM and gliomedin acting through their axonal receptor neurofascin 186 (NF186). This glial signal is distinct from a second paranodal junction-dependent mechanism. NrCAM and gliomedin cooperate to capture Na+ channels at heminodes before fusion into mature nodes.\",\n      \"method\": \"Gliomedin/NrCAM knockout mice, immunostaining during PNS development, electron microscopy\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mice with mechanistically defined two-step nodal assembly pathway; replicated by subsequent long-term maintenance paper\",\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 neural cells. Genetic deletion of NrCAM causes misprojection of thalamic axons caudally at the ventral telencephalon and striking mistargeting of motor and somatosensory thalamic axons to primary visual cortex. NrCAM is required for Sema3F-induced growth cone collapse in thalamic neuron cultures, consistent with a role in Sema3F-induced axon repulsion via the NrCAM-Npn-2 complex.\",\n      \"method\": \"NrCAM null mouse, anterograde axon tracing, co-immunoprecipitation of NrCAM-Npn-2 complex, growth cone collapse assay, visual evoked potentials\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of receptor complex, genetic null with in vivo axon tracing, in vitro functional assay; multiple orthogonal methods\",\n      \"pmids\": [\"21273439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sema6D and Nr-CAM are expressed on midline radial glia and Plexin-A1 on chiasm neurons; Plexin-A1 and Nr-CAM are also expressed on contralateral RGCs. Nr-CAM functions as a receptor for Sema6D. Sema6D in combination with Nr-CAM and Plexin-A1 converts Sema6D-mediated repulsion to growth promotion for contralateral RGCs. All three (Sema6D, Plexin-A1, NrCAM) are required for efficient RGC decussation.\",\n      \"method\": \"Knockout mouse analysis, in vitro growth assays, receptor identification experiments, genetic interaction analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockout analyses, functional conversion of repulsion to attraction, receptor identification for Sema6D; orthogonal in vitro and in vivo approaches\",\n      \"pmids\": [\"22632726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NrCAM contributes to mediolateral retinocollicular axon targeting through regulation of RGC axon branch orientation. EphB2 tyrosine kinase (but not kinase-dead EphB2) phosphorylates NrCAM at a conserved tyrosine in the FIGQY ankyrin-binding motif, perturbing ankyrin recruitment in NrCAM-transfected HEK293 cells. In vivo, phospho-FIGQY NrCAM in SC is decreased in EphB1/3 null mice and increased in constitutively active EphB2 mice.\",\n      \"method\": \"NrCAM null mouse axon tracing, EphB kinase phosphorylation assay in HEK293 cells, kinase-dead mutant, EphB null mouse analysis, ankyrin recruitment assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct kinase assay with mutagenesis, in vivo genetic confirmation in multiple mouse models, ankyrin-binding functional consequence\",\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 the extracellular Ig1 domain. NrCAM deletion elevates spine density on apical dendrites and increases mEPSC frequency. Recombinant Sema3F-Fc induced spine retraction on wild-type but not NrCAM-null neurons; re-expression of NrCAM rescued the response. Trans heterozygous genetic interaction confirmed NrCAM and Sema3F pathways interact in vivo.\",\n      \"method\": \"NrCAM null mouse, co-immunoprecipitation, spine density quantification, electron microscopy, whole-cell electrophysiology, rescue experiments, trans heterozygous genetic interaction\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP of holoreceptor complex, KO phenotype, rescue, electrophysiology, genetic epistasis; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"25143608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Long-term maintenance of Na+ channels at PNS nodes of Ranvier requires axoglial contact mediated by both gliomedin and NrCAM together. Mice lacking both molecules (but not either alone) show gradual loss of nodal Na+ channels and other axonal components, formation of binary nodes, dysregulation of nodal gap length, and neurological abnormalities. Node disintegration follows the reverse order of assembly: NF186 disappears first, then Na+ channels and ankyrinG, then βIV spectrin.\",\n      \"method\": \"Gliomedin/NrCAM double knockout mouse, immunostaining, electron microscopy, electrophysiology, behavioral analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double knockout genetic analysis with ordered molecular disassembly, electrophysiology, EM; extends prior single-KO work\",\n      \"pmids\": [\"24719088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NrCAM activates MAPK/Erk and PI3K/Akt signaling pathways via ectodomain shedding and binding to EGFR and α4β1 integrins. These pathways in turn upregulate NrCAM expression through the GSK3β/β-catenin axis, establishing positive feedback loops. NrCAM depletion inhibited thyroid cancer cell growth and invasiveness.\",\n      \"method\": \"NrCAM knockdown and overexpression in thyroid cancer cells, phosphorylation assays, co-immunoprecipitation, nude mouse xenograft, transgenic BrafV600E mouse\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, signaling assays, in vivo models; single lab but multiple cell and animal model approaches\",\n      \"pmids\": [\"27732334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NrCAM functions as a substrate for ADAM10 metalloprotease cleavage. ADAM10 controls NrCAM surface levels and regulates neurite outgrowth in an NrCAM-dependent manner in vitro. However, ADAM10 cleavage of NrCAM (unlike APP) is not stimulated by the ADAM10 activator acitretin, suggesting substrate-selective ADAM10 activation is feasible and that NrCAM can serve as a biomarker of basal (non-stimulated) ADAM10 activity.\",\n      \"method\": \"ADAM10 activity assay, NrCAM surface level quantification, neurite outgrowth assay, human CSF proteomics from clinical trial\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct substrate identification with functional consequence (neurite outgrowth), selectivity demonstrated by comparison to APP, validated in human CSF proteomics\",\n      \"pmids\": [\"30833305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NrCAM promotes clustering of the Sema3F holoreceptor complex by interfacing with Neuropilin-2 (Npn-2) and the PDZ scaffold protein SAP102. NrCAM-induced receptor clustering stimulates Rap-GAP activity of PlexinA3 (PlexA3) within the holoreceptor complex, which inhibits Rap1-GTPase and inactivates adhesive β1 integrins, mediating Sema3F-induced spine pruning during adolescence. Conditional inducible NrCAM deletion (Nex1Cre-ERT2:NrCAMflox/flox) showed NrCAM acts cell-autonomously in pyramidal neurons.\",\n      \"method\": \"Conditional inducible knockout mouse, molecular modeling, holoreceptor complex assembly assay, Rap-GAP activity assay, Rap1-GTPase assay, β1 integrin activity assay, spine density quantification\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO, enzymatic (Rap-GAP) assay, integrin activity measurement, receptor clustering; multiple orthogonal mechanistic approaches\",\n      \"pmids\": [\"29415226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NrCAM mediates fasciculation of axon fibers in the stria terminalis, regulating amygdala-BNST connectivity. NrCAM null mice show pronounced defasciculation and misprojection of fibers in the stria terminalis and are impaired in context-dependent (but not cued) fear conditioning, linking NrCAM-mediated axon fasciculation to amygdalar-BNST circuit function.\",\n      \"method\": \"NrCAM null mouse, neurofilament immunohistochemistry of fiber tracts, contextual vs. cued fear conditioning behavioral testing\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null with defined anatomical and behavioral phenotypes; single lab with orthogonal morphological and behavioral readouts\",\n      \"pmids\": [\"30766872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Neurocan (a chondroitin sulfate proteoglycan) inhibits Sema3F-induced spine elimination through binding to NrCAM. Cell binding and ELISA assays demonstrated association of Neurocan with NrCAM. Neurocan blocked Sema3F-induced morphological retraction in COS-7 cells mediated through NrCAM, Npn-2, and PlexinA3. Glycosaminoglycan chains of Neurocan (but not the C-terminal sushi domain) were required for this inhibition.\",\n      \"method\": \"Cell binding assay, ELISA, COS-7 cell morphology assay, cortical neuron culture spine assay, domain deletion analysis\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct binding assay, functional blocking in two cell systems, domain requirement established; single lab\",\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 variant) at the expense of Nrcam-10 in injured DRG. Antisense oligonucleotides (ASO) targeting exon 10 attenuated mechanical allodynia, thermal hyperalgesia, and cold allodynia in SNL and CCD models in both male and female mice.\",\n      \"method\": \"RNA sequencing, ASO treatment (DRG microinjection and intrathecal), behavioral pain assays (von Frey, thermal, cold plate)\",\n      \"journal\": \"The journal of pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific ASO intervention with defined splicing change, multiple pain behavioral readouts, two injury models; single lab\",\n      \"pmids\": [\"31917219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NrCAM and Ankyrin B mediate perisomatic synaptic contact between CCK-basket cells (CCK-BCs) and pyramidal neurons (PNs) in mouse medial prefrontal cortex. NrCAM-null mice show significant decreases in CCK-BC (VGLUT3+ and VGAT+) synaptic puncta on PN soma but no decrease in PV-BC puncta or cell loss. Ankyrin B deletion specifically from PNs also reduces VGLUT3+ CCK-BC puncta, establishing that postsynaptic NrCAM-Ankyrin B interaction is required for CCK-BC synapse formation.\",\n      \"method\": \"NrCAM null mouse, conditional Ankyrin B deletion (Nex1Cre-ERT2:Ank2flox/flox), CCK-BC reporter mouse (Sncg-tdTomato), immunolabeling, confocal quantification\",\n      \"journal\": \"Current research in neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic models (NrCAM KO and conditional Ank2 KO) converging on same synaptic phenotype; single lab\",\n      \"pmids\": [\"40276719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NrCAM activates the NF-κB signaling pathway by competitively binding to SUMO-1, reducing IκBα SUMOylation and increasing IκBα phosphorylation and degradation, thereby promoting NF-κB-dependent Th17 cell differentiation. NrCAM overexpression increased IL-21 via NF-κB (p65 binding to IL-21 promoter), and NF-κB inhibitor BAY11-7082 partially reversed NrCAM's effects.\",\n      \"method\": \"NrCAM overexpression and knockdown in CD4+ T cells, flow cytometry for Th17 markers, co-immunoprecipitation of NrCAM-SUMO-1, p-IκBα western blot, ChIP for p65 on IL-21 promoter, NF-κB inhibitor treatment\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP of NrCAM-SUMO-1 complex, ChIP, multiple signaling readouts; single lab, non-neural context but mechanistically informative\",\n      \"pmids\": [\"39155774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In hepatocellular carcinoma (HCC), NrCAM promotes liver cancer stem cell (LCSC) migration, invasion, and metastasis by activating epithelial-mesenchymal transition (EMT) and matrix metalloproteinases (MMPs) through the MACF1-mediated β-catenin signaling pathway in LCSCs.\",\n      \"method\": \"MYC-driven LCSC organoids, NrCAM knockdown and overexpression, invasion/migration assays, in vivo tumor allografts (intra-hepatic and lung metastasis), scRNA-seq, MACF1/β-catenin pathway analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional studies with pathway identification; single lab, specific mechanistic pathway (MACF1/β-catenin)\",\n      \"pmids\": [\"37993901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rbfox1 (RNA-binding Fox1) regulates alternative splicing of NrCAM exon 10 in DRG after spinal nerve ligation. Downregulation of Rbfox1 following nerve injury amplifies exon 10 insertion (L-Nrcam increase, S-Nrcam decrease). Restoring Rbfox1 mitigates nociceptive hypersensitivity; mimicking Rbfox1 downregulation generates neuropathic pain symptoms.\",\n      \"method\": \"Transcriptome profiling (RNA-seq), bioinformatic splicing analysis, Rbfox1 overexpression/knockdown in DRG, splicing isoform quantification, behavioral pain assays\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of splicing regulator with functional rescue/phenocopy; extends prior Nrcam splicing/pain work; single lab\",\n      \"pmids\": [\"38241164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The NRCAM proteoform with microexons 5 and 19 skipped (Δex5Δex19 NRCAM) is uniformly expressed in pediatric high-grade gliomas but not normal brain. This specific splice variant (not full-length NrCAM) is essential for pHGG cell migration, invasion in vitro, and tumor growth in vivo. A monoclonal antibody selective for Δex5Δex19 NRCAM enables T-cell-mediated killing of pHGG cells via an FcRI-based universal immune receptor.\",\n      \"method\": \"Bulk and single-nuclei short- and long-read RNA-seq, loss-of-function assays (migration/invasion in vitro), in vivo tumor growth, monoclonal antibody development, T-cell killing assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — RNA-seq identification, loss-of-function in vitro and in vivo, antibody selectivity validation; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"40782352\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NrCAM is a transmembrane cell adhesion molecule of the L1/Ig superfamily whose cytoplasmic domain links to ankyrin (via the FIGQY motif) and the actin cytoskeleton (via lipid raft-mediated coupling and FNIII cis-interactions), while its extracellular Ig and FNIII domains mediate homophilic binding and heterophilic interactions with axonin-1/TAG-1, contactin/F3, neurofascin, F11, RPTPβ, Sema6D, and integrins to regulate axon guidance, node of Ranvier Na⁺ channel clustering, dendritic spine pruning (as part of the Sema3F/Npn-2/PlexA3 holoreceptor complex that activates Rap-GAP/Rap1 to inactivate β1 integrins), perisomatic CCK-basket cell synapse formation (via Ankyrin B), and—through ectodomain shedding—oncogenic ERK/AKT activation; NrCAM expression is transcriptionally driven by the β-catenin/LEF-1 pathway, post-translationally regulated by EphB2 phosphorylation at FIGQY and ADAM10 cleavage, and functionally modulated by alternative splicing of exon 10 (regulated by Rbfox1 in DRG) which controls neuropathic pain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NRCAM (Nr-CAM/Bravo) is a neural transmembrane glycoprotein of the L1/Ig adhesion superfamily, built from six Ig-like domains, five fibronectin type III repeats, a transmembrane segment, and a short ankyrin-binding cytoplasmic tail, that organizes axon guidance, node of Ranvier assembly, and synapse formation through homophilic and heterophilic adhesion [#0, #1]. Its extracellular domains engage a wide partner repertoire—contactin/F3, axonin-1/TAG-1, neurofascin, F11, and RPTPβ—to drive neurite outgrowth, neuron-glia contact, and directional pathfinding of commissural and retinal ganglion cell axons at the midline and optic chiasm [#3, #5, #6, #9, #21], while its cytoplasmic FIGQY motif binds ankyrins to couple the membrane to the cytoskeleton, a linkage further reinforced by lipid-raft partitioning and FNIII cis-interactions that tether NrCAM to retrograde actin flow [#4, #11, #18]. At nodes of Ranvier and axon initial segments, glial NrCAM acting with gliomedin and neurofascin-186 captures and stabilizes voltage-gated Na⁺ channels and ankyrinG, and is required for both initial clustering and long-term nodal maintenance [#7, #13, #17, #22, #27]. Postsynaptically, NrCAM nucleates the Sema3F holoreceptor (with Neuropilin-2 and PlexinA3) and, via SAP102, activates PlexinA3 Rap-GAP activity to inactivate β1 integrins and drive dendritic spine pruning, and through ankyrin B it builds perisomatic CCK-basket cell synapses [#23, #26, #30, #34]. NrCAM activity is tuned by EphB2 phosphorylation of the FIGQY motif, by ADAM10/metalloprotease ectodomain shedding that liberates a fragment activating ERK/AKT signaling, by β-catenin/LEF-1 transcriptional control, and by Rbfox1-regulated exon 10 splicing that governs neuropathic pain [#16, #19, #25, #29, #33, #37]. In cancer, NrCAM ectodomain shedding and integrin/EGFR engagement drive ERK/AKT and β-catenin signaling to promote transformation, invasion, and metastasis, and a tumor-specific Δex5Δex19 splice proteoform is essential for pediatric high-grade glioma growth [#16, #19, #28, #36, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing NrCAM as a discrete molecular entity defined its domain architecture and placed it as a candidate neural adhesion receptor.\",\n      \"evidence\": \"cDNA cloning, protein purification, and N-terminal sequencing of the 145-kDa neural glycoprotein\",\n      \"pmids\": [\"2045418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function inferred from structure only\", \"No binding partners yet identified\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstrating that NrCAM mediates both homophilic and heterophilic adhesion, and is post-translationally cleaved into an alpha/beta heterodimer, defined it functionally as an adhesion molecule.\",\n      \"evidence\": \"Cell aggregation and substrate binding assays with recombinant FGTNr, L-cell transfection, plus SDS-PAGE/sequence analysis of the cleaved chains\",\n      \"pmids\": [\"1527169\", \"1512296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific heterophilic ligands unidentified\", \"Functional role of cleavage not established\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identifying F11/contactin as a direct heterophilic ligand connected NrCAM adhesion to a concrete neurite-outgrowth output and mapped the binding interface.\",\n      \"evidence\": \"Neurite outgrowth on immobilized F11, antibody blocking, COS-cell binding, and F11 deletion mutants\",\n      \"pmids\": [\"8274278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from the F11-NrCAM interaction unresolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showing the cytoplasmic domain binds ankyrins established the membrane-cytoskeleton linkage that underlies NrCAM clustering and stabilization.\",\n      \"evidence\": \"Biochemical co-association and protein quantification from brain membrane fractions\",\n      \"pmids\": [\"7961622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence determinant (FIGQY) not yet defined\", \"Functional consequence in vivo untested\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrating that floor-plate NrCAM engages growth-cone axonin-1 to direct commissural midline crossing gave NrCAM a defined in vivo guidance function.\",\n      \"evidence\": \"In vivo antibody perturbation in chick spinal cord and histological axon trajectory analysis, plus axonin-1/NrCAM binding on peripheral glia\",\n      \"pmids\": [\"7541632\", \"7490283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transduction converting adhesion to guidance unknown\", \"Receptor-side cytoplasmic mechanism undefined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Co-localizing NrCAM with neurofascin, ankyrinG, and Na+ channels at nodes of Ranvier, and demonstrating direct NrCAM-neurofascin binding, positioned NrCAM at the heart of nodal assembly.\",\n      \"evidence\": \"Isoform-specific antibody immunofluorescence, COS-cell binding, immunoprecipitation, and reciprocal neurite outgrowth assays\",\n      \"pmids\": [\"8947556\", \"8922386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal requirement for Na+ channel clustering not yet tested\", \"Glial vs axonal contributions unseparated\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing RPTPβ binds a contactin-NrCAM complex linked NrCAM adhesion to a phosphatase-coupled neuronal differentiation signal.\",\n      \"evidence\": \"Co-immunoprecipitation, antibody-blocked neurite outgrowth, and transfected-cell differentiation co-culture\",\n      \"pmids\": [\"9049255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase substrates downstream of the complex unidentified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining NrCAM as a substrate ligand for axonin-1 and F3 receptors, and coupling F3-induced clustering to retrograde actin flow, mechanistically connected adhesion to growth-cone motility.\",\n      \"evidence\": \"Recombinant Fc fusion substrate assays, in ovo injection, microsphere tracking, and cytochalasin B disruption of retrograde movement\",\n      \"pmids\": [\"10328925\", \"10462518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular bridge between cytoplasmic tail and actin not defined\", \"Lipid-raft requirement not yet established\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic null mice and Fc-perturbation cocultures established that NrCAM is functionally required in vivo for cerebellar neurite outgrowth, nodal Na+ channel clustering, and (with ankyrin-B) lens fiber organization.\",\n      \"evidence\": \"NrCAM knockout and ankyrin-B mutant mice, contactin-substrate neurite assays, myelinating DRG-Schwann cocultures, histology and EM\",\n      \"pmids\": [\"11564762\", \"11449000\", \"11728309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with L1-family members complicates single-KO interpretation\", \"Temporal sequence of nodal assembly not yet resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying NrCAM as a direct β-catenin/LEF-1 transcriptional target and a transforming gene shifted it from a developmental adhesion molecule to an oncogenic effector.\",\n      \"evidence\": \"Microarray, promoter-reporter assays with LEF/TCF site mutation, retroviral transduction, motility/growth assays, and nude-mouse xenografts\",\n      \"pmids\": [\"12183361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which surface NrCAM promotes motility unresolved at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Temporal analysis in null mice showed NrCAM precedes and locally captures Na+ channels at developing nodes, defining it as an early glial-contact-dependent nodal organizer.\",\n      \"evidence\": \"NrCAM null mouse with quantitative developmental immunostaining of Na+ channel/ankyrinG timing\",\n      \"pmids\": [\"14602817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of cooperating glial ligand not yet defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Biophysical dissection showed NrCAM-actin coupling requires both cytoplasmic and FNIII cis-interactions plus lipid-raft partitioning, refining the mechanics of adhesion-driven traction.\",\n      \"evidence\": \"Optical tweezers, single-particle tracking, FRAP, NrCAM deletion mutants, and cholesterol depletion\",\n      \"pmids\": [\"15254265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific raft-resident adaptors not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating metalloprotease ectodomain shedding that activates ERK/AKT via integrin association established a soluble-fragment signaling mechanism for NrCAM oncogenicity.\",\n      \"evidence\": \"Shedding detection, conditioned-medium assays, co-IP with α4β1 integrins, ERK/AKT phosphorylation, siRNA, and ectodomain-expression tumor assays\",\n      \"pmids\": [\"16357171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific sheddase identity not pinned down at this stage\", \"Receptor for the shed ectodomain incompletely defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying a unique PDZ-binding motif binding SAP90/PSD95 and SAP97, and a role in retinal chiasm guidance, extended NrCAM's scaffold interactions and CNS guidance functions.\",\n      \"evidence\": \"PDZ binding and mutagenesis in COS-7 cells, co-localization, NrCAM null axon tracing, and chiasm-cell neurite assays\",\n      \"pmids\": [\"16882004\", \"16701205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PDZ scaffolding at synapses untested here\", \"Relationship to EphB guidance program parallel but mechanistically separate\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovering an NrCAM-Neuropilin-2 complex required for Sema3F-induced growth cone collapse assigned NrCAM a co-receptor role in semaphorin-mediated axon repulsion and thalamocortical targeting.\",\n      \"evidence\": \"NrCAM null mouse axon tracing, co-IP of NrCAM-Npn-2, growth cone collapse assays, and visual evoked potentials\",\n      \"pmids\": [\"21273439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling output of the complex not yet defined\", \"Plexin involvement not yet incorporated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing NrCAM acts as a Sema6D receptor with Plexin-A1 that converts repulsion to growth promotion clarified how a single ligand can be reinterpreted to drive RGC decussation.\",\n      \"evidence\": \"Knockout mouse analyses, in vitro growth assays, and receptor identification with genetic interaction tests\",\n      \"pmids\": [\"22632726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the repulsion-to-attraction switch unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining NrCAM as a component of the Sema3F holoreceptor that restricts dendritic spine density established its postsynaptic role in spine pruning.\",\n      \"evidence\": \"NrCAM null mouse, co-IP of Npn-2/PlexA3, spine quantification, EM, electrophysiology, and Sema3F-Fc rescue\",\n      \"pmids\": [\"25143608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular effector linking the complex to spine retraction not yet identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating EphB2 kinase phosphorylates the NrCAM FIGQY motif to perturb ankyrin recruitment defined a switch coupling Eph signaling to NrCAM-cytoskeleton uncoupling in axon targeting.\",\n      \"evidence\": \"EphB kinase and kinase-dead assays in HEK293, ankyrin-recruitment assays, NrCAM null axon tracing, and EphB null/constitutively active mouse analysis\",\n      \"pmids\": [\"24023801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo dynamics of phospho-FIGQY regulation incompletely mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistic dissection showed NrCAM clusters the Sema3F holoreceptor via SAP102 to activate PlexinA3 Rap-GAP, inactivating β1 integrins for spine pruning, and identified ADAM10 as the sheddase controlling surface NrCAM.\",\n      \"evidence\": \"Conditional inducible NrCAM knockout, Rap-GAP/Rap1-GTPase and β1-integrin activity assays, modeling, ADAM10 activity assays, neurite outgrowth, and human CSF proteomics\",\n      \"pmids\": [\"29415226\", \"30833305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance of adhesion vs pruning signaling unresolved\", \"ADAM10-NrCAM cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking NrCAM-mediated stria terminalis fasciculation to contextual fear behavior connected its axon-bundling role to circuit-level function.\",\n      \"evidence\": \"NrCAM null mouse, neurofilament immunohistochemistry, and contextual vs cued fear conditioning\",\n      \"pmids\": [\"30766872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of fasciculation in this tract not dissected\", \"Single lab; behavioral causality indirect\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying Neurocan as an NrCAM-binding inhibitor of Sema3F-induced spine elimination introduced an extracellular brake on the pruning pathway.\",\n      \"evidence\": \"Cell binding/ELISA, COS-7 and cortical neuron morphology assays, and Neurocan domain deletions\",\n      \"pmids\": [\"30356641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and competition with Sema3F not quantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing injury-induced exon 10 inclusion drives neuropathic pain, and that Rbfox1 governs this splicing, established a splice-isoform mechanism amenable to ASO intervention.\",\n      \"evidence\": \"RNA-seq, ASO targeting exon 10, Rbfox1 overexpression/knockdown in DRG, and behavioral pain assays in two injury models\",\n      \"pmids\": [\"31917219\", \"38241164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the +10 isoform alters NrCAM adhesion/signaling in nociceptors undefined\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining a postsynaptic NrCAM-ankyrin B requirement for CCK-basket cell perisomatic synapses extended NrCAM's role to inhibitory synapse specificity.\",\n      \"evidence\": \"NrCAM null and conditional Ank2 knockout mice with CCK-BC reporter and confocal puncta quantification\",\n      \"pmids\": [\"40276719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-synaptic partner on CCK-BC axons not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating NrCAM activates NF-κB by competing for SUMO-1 to destabilize IκBα, promoting Th17 differentiation, extended NrCAM signaling beyond the nervous system.\",\n      \"evidence\": \"NrCAM overexpression/knockdown in CD4+ T cells, co-IP with SUMO-1, p-IκBα western, p65 ChIP on IL-21 promoter, and NF-κB inhibitor\",\n      \"pmids\": [\"39155774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a transmembrane CAM accesses cytoplasmic SUMO-1 mechanistically unclear\", \"Single lab, non-neural context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying NrCAM-driven MACF1/β-catenin signaling in hepatocellular carcinoma stem cells reinforced its pro-metastatic role via EMT and MMP induction.\",\n      \"evidence\": \"MYC-driven LCSC organoids, knockdown/overexpression, invasion assays, allografts, scRNA-seq, and pathway analysis\",\n      \"pmids\": [\"37993901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical link between NrCAM and MACF1 not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovering a tumor-restricted Δex5Δex19 NRCAM proteoform essential for pediatric high-grade glioma and targetable by a selective antibody established splice-variant-specific NrCAM as a therapeutic target.\",\n      \"evidence\": \"Short- and long-read RNA-seq, loss-of-function migration/invasion and in vivo growth assays, and a variant-selective monoclonal antibody enabling T-cell killing\",\n      \"pmids\": [\"40782352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which microexon skipping confers tumor dependence unresolved\", \"Functional difference between Δex5Δex19 and full-length signaling undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and signaling rules that determine whether NrCAM acts as an adhesive stabilizer versus a repulsion/pruning effector, and how its many splice isoforms reprogram these outputs across tissues, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of NrCAM bound to its ligands\", \"Isoform-specific binding and signaling outputs not systematically compared\", \"Mechanism converting adhesion to growth-cone steering still inferential\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 3, 6, 8, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [23, 24, 26, 30]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 11, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [20, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 7, 20]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [11, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 12, 21, 23, 24, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 19, 28, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 19, 28, 36, 38]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 13, 17, 22, 27]}\n    ],\n    \"complexes\": [\n      \"Sema3F holoreceptor (NrCAM/Neuropilin-2/PlexinA3)\",\n      \"node of Ranvier Na+ channel complex (with neurofascin/ankyrinG)\",\n      \"contactin/NrCAM-RPTPβ complex\"\n    ],\n    \"partners\": [\n      \"CNTN1\",\n      \"CNTN2\",\n      \"NFASC\",\n      \"ANK2\",\n      \"NRP2\",\n      \"PLXNA3\",\n      \"PTPRZ1\",\n      \"DLG1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}