{"gene":"NFASC","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1992,"finding":"Neurofascin was structurally characterized from chick brain as a member of the L1 subgroup of the immunoglobulin superfamily, comprising six C2-type Ig-like domains, four fibronectin type III repeats, a proline-alanine-threonine (PAT)-rich domain, a transmembrane segment, and a cytoplasmic domain. The gene is alternatively spliced, generating multiple isoforms with different molecular masses. Neurofascin promotes axonal growth and fasciculation as shown by antibody perturbation experiments.","method":"cDNA cloning and sequencing, Northern blot, immunoaffinity chromatography, deglycosylation assays, antibody perturbation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — original structural characterization by cDNA sequencing plus protein biochemistry, foundational study","pmids":["1377696"],"is_preprint":false},{"year":1996,"finding":"A mucin-domain-containing isoform of neurofascin (NF186) lacking the third FNIII domain was found concentrated at axon initial segments and nodes of Ranvier, co-localizing with ankyrinG and voltage-dependent sodium channels. NrCAM was also co-localized at nodes of Ranvier and axon initial segments. These define neurofascin as a key ankyrin-binding cell adhesion molecule organizing the nodal axon segment.","method":"Isoform-specific antibody generation, full-length cDNA isolation, immunofluorescence co-localization in myelinated nerve","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiments with isoform-specific antibodies, replicated across axon initial segments and nodes","pmids":["8947556"],"is_preprint":false},{"year":1997,"finding":"Phosphorylation of the conserved FIGQY tyrosine in the cytoplasmic domain of neurofascin regulates its binding to ankyrin: tyrosine-phosphorylated neurofascin does not bind ankyrin, while non-phosphorylated neurofascin binds ankyrin and mediates cell aggregation. Phosphorylation state governs neurofascin-dependent cell sorting when expressed in neuroblastoma cells.","method":"Phosphorylation state manipulation, cell aggregation assays, cell sorting experiments in neuroblastoma cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — functional mutagenesis/phosphorylation state experiments with clear cellular phenotypic readout (cell aggregation, sorting)","pmids":["9371782"],"is_preprint":false},{"year":1998,"finding":"The cytoplasmic domain of neurofascin dimerizes in solution and the sequence Ser56-Tyr81 is necessary and sufficient for ankyrin binding. Mutation of the FIGQY tyrosine (Y81H/A/E) or F77A or E73Q greatly impairs neurofascin-ankyrin interaction. Transfected neurofascin recruits GFP-tagged 270-kDa ankyrinG to the plasma membrane of HEK293 cells, establishing the structural basis for ankyrin recruitment.","method":"Deletion and point mutant analysis, GFP-ankyrinG recruitment assay in HEK293 cells, biochemical characterization of cytoplasmic domain dimerization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro structural analysis plus mutagenesis with live-cell functional readout","pmids":["9804856"],"is_preprint":false},{"year":1998,"finding":"Neurofascin binds to tenascin-R, axonin-1, and F11 in addition to NrCAM. Alternative splicing of neurofascin isoforms differentially regulates binding to axonin-1 and tenascin-R (but not F11). Tenascin-R presence shifts cell receptor usage from NrCAM to axonin-1 and F11 on tectal cells, as shown by competition binding assays and in vitro neurite outgrowth experiments.","method":"Cellular binding assays, competition binding assays, in vitro neurite outgrowth assays on neurofascin-Fc substrate","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal binding and functional assays establishing ligand specificity and isoform-dependent interactions","pmids":["9722619"],"is_preprint":false},{"year":2001,"finding":"AnkyrinG is required for the assembly of neurofascin (and NrCAM) at Purkinje neuron axon initial segments. In mice lacking cerebellar ankyrinG, neurofascin, NrCAM, betaIV spectrin, and Nav1.6 are all absent from axon initial segments, demonstrating that ankyrinG coordinates the physiological assembly of this protein complex.","method":"AnkyrinG knockout mouse analysis, immunofluorescence of axon initial segments, postnatal developmental time course","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function mouse model with clear molecular phenotype at axon initial segments, multiple protein markers examined","pmids":["11724816"],"is_preprint":false},{"year":2001,"finding":"The sodium channel beta1 (and beta3) subunits associate with neurofascin through their extracellular Ig-like domains; the first Ig-like domain and second FNIII domain of neurofascin mediate this interaction. Beta1 subunits co-localize with neurofascin at nodes of Ranvier in sciatic nerve axons, and the association begins during early node formation (postnatal day 5), suggesting neurofascin facilitates recruitment of sodium channel complexes to nodes.","method":"Co-immunoprecipitation, cell binding assays, immunofluorescence co-localization in sciatic nerve, developmental time course","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal domain-mapping pulldown combined with in vivo co-localization and developmental analysis","pmids":["11470829"],"is_preprint":false},{"year":2001,"finding":"Neurofascin interacts intracellularly with syntenin-1 (but not syntenin-2) through the C-terminus of neurofascin and the second PDZ domain of syntenin-1, as confirmed by yeast two-hybrid, ligand-overlay assay, surface plasmon resonance, and co-localization in heterologous cells. This interaction is specific to neurofascin within the L1 subgroup and may link it to trafficking or signaling pathways.","method":"Yeast two-hybrid screening, ligand-overlay assay, surface plasmon resonance, co-localization in heterologous cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods confirm interaction; interaction specificity established by negative controls with L1, NrCAM","pmids":["11152476"],"is_preprint":false},{"year":2002,"finding":"The glial isoform NF155 acts as a glial receptor for the axonal paranodin/Caspr-contactin cis-complex at paranodal axoglial junctions. The extracellular domain of NF155 binds specifically to cells expressing the Caspr-contactin complex, and also pulls down the complex from brain lysates in vitro. NF155 antibodies and recombinant NF155 extracellular domain inhibit myelination in co-culture, demonstrating that this interaction is required for axoglial junction formation.","method":"Cell-binding assays with transfected cells, brain lysate pulldown, myelinating co-culture inhibition assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro binding reconstitution plus functional myelination assay with blocking constructs, multiple orthogonal approaches","pmids":["11839274"],"is_preprint":false},{"year":2004,"finding":"AnkyrinG-dependent localization of NF186 at the Purkinje axon initial segment forms a subcellular gradient that directs GABAergic basket interneuron innervation. In the absence of neurofascin gradient, basket axons lose directional growth and follow NF186 to ectopic locations. Disruption of NF186-ankyrinG interactions at the AIS reduces pinceau synapse formation.","method":"BAC transgenic reporter mice, conditional neurofascin manipulation, analysis of basket axon innervation patterns, disruption of NF186-ankyrinG interactions","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic manipulation with clear synaptic targeting phenotype, multiple lines of evidence","pmids":["15479642"],"is_preprint":false},{"year":2007,"finding":"Anti-neurofascin autoantibodies found in MS patients recognize both NF186 (neuronal, at nodes of Ranvier) and NF155 (oligodendrocyte isoform). These antibodies inhibit axonal conduction in hippocampal slice cultures in a complement-dependent manner. Co-transfer of anti-neurofascin antibodies with MOG-specific T cells in a rat EAE model caused selective targeting of nodes of Ranvier, complement deposition, axonal injury, and disease exacerbation, establishing a direct pathogenic mechanism.","method":"Proteomics-based antigen identification, hippocampal slice culture electrophysiology, passive transfer EAE model in rats with co-transfer of antibodies and T cells","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — in vitro functional assay plus in vivo passive transfer model demonstrating direct pathogenicity of anti-neurofascin antibodies","pmids":["17846150"],"is_preprint":false},{"year":2009,"finding":"Myelinating glia-specific conditional knockout of Nfasc(NF155) in mice results in failure of paranodal axoglial junctions to form, failure of axonal domain segregation (Caspr, Cont, potassium channels), severe ataxia, motor paresis, dramatic reduction in nerve conduction velocities, and death by postnatal week 3. Inducible adult ablation of NF155 causes gradual loss of paranodal junctions as protein levels drop, demonstrating that NF155 is also required for maintenance of axonal domains. This provides direct evidence that paranodal axoglial junctions function as a fence for axonal domain organization.","method":"Conditional (PLP-Cre) and inducible (PLP-CreER) knockout mice, electrophysiology of peripheral nerves, immunofluorescence for axonal domain markers","journal":"Journal of neuroscience research","confidence":"High","confidence_rationale":"Tier 2 — both developmental and adult conditional KO with quantitative electrophysiology and molecular marker analysis; strong evidence from multiple approaches","pmids":["19185024"],"is_preprint":false},{"year":2010,"finding":"In vivo deletion of Ig domains 5 and 6 from Nfasc(NF155) phenocopies complete ablation of NF155 — paranodal septate junctions are absent, Caspr and contactin diffuse from paranodes, and juxtaparanodal potassium channels redistribute toward nodes. These same domains are dispensable for nodal Nfasc(NF186) function. In vitro binding assays confirm that Ig5-6 are required for the association of NF155 with contactin, establishing the molecular basis for the paranodal tripartite complex.","method":"In vivo knock-in mouse with Ig5-6 deletion, immunofluorescence of paranodal markers, in vitro binding assays with deletion constructs","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo domain deletion combined with in vitro binding assays, clear molecular and phenotypic consequences","pmids":["20371806"],"is_preprint":false}],"current_model":"Neurofascin (NFASC) is an alternatively spliced L1-family immunoglobulin cell adhesion molecule whose two principal isoforms serve distinct roles: NF186 (neuronal, containing a mucin domain) localizes to axon initial segments and nodes of Ranvier via ankyrinG binding through its cytoplasmic FIGQY motif — a binding regulated by tyrosine phosphorylation — where it recruits voltage-gated sodium channel complexes and organizes GABAergic synapses; while NF155 (glial, expressed by oligodendrocytes) mediates paranodal axoglial junctions by binding the axonal Caspr-contactin complex through its Ig domains 5 and 6, thereby establishing the paranodal diffusion barrier required for axonal domain segregation and efficient saltatory conduction, with NF155 loss causing junction failure, potassium channel redistribution, and severe conduction deficits."},"narrative":{"teleology":[{"year":1992,"claim":"Identification of neurofascin as an alternatively spliced L1-family Ig-superfamily member established the molecular framework for understanding how a single gene generates functionally distinct adhesion molecules in the nervous system.","evidence":"cDNA cloning, protein biochemistry, and antibody perturbation of axon growth in chick brain","pmids":["1377696"],"confidence":"High","gaps":["Functional roles of individual splice isoforms were not defined","Intracellular binding partners were unknown","Relevance to myelinated axon organization was not yet explored"]},{"year":1996,"claim":"Discovery that the NF186 isoform concentrates at nodes of Ranvier and axon initial segments together with ankyrinG and sodium channels resolved where neurofascin functions and implicated it as a scaffold organizer of excitable axonal domains.","evidence":"Isoform-specific antibody generation and immunofluorescence co-localization in myelinated nerves","pmids":["8947556"],"confidence":"High","gaps":["Direct binding between neurofascin and ankyrinG had not been biochemically demonstrated","Whether neurofascin was required or merely co-localized was unresolved"]},{"year":1998,"claim":"Mapping the ankyrin-binding site to the cytoplasmic FIGQY motif and showing that tyrosine phosphorylation abolishes this interaction provided a regulatory switch mechanism controlling neurofascin's anchorage to the spectrin–actin cytoskeleton.","evidence":"Phosphorylation-state manipulation and cell aggregation/sorting assays in neuroblastoma cells; deletion/point-mutant analysis with GFP-ankyrinG recruitment in HEK293 cells","pmids":["9371782","9804856"],"confidence":"High","gaps":["The kinase and phosphatase controlling FIGQY phosphorylation in vivo were not identified","Whether phosphorylation-dependent switching operates at nodes versus AIS was unknown"]},{"year":1998,"claim":"Demonstration that neurofascin binds tenascin-R, axonin-1, and F11 in an isoform-dependent manner expanded its extracellular interaction repertoire beyond homophilic adhesion, linking alternative splicing to ligand selectivity.","evidence":"Cellular binding assays, competition experiments, and neurite outgrowth assays on neurofascin-Fc substrates","pmids":["9722619"],"confidence":"High","gaps":["In vivo relevance of tenascin-R modulation of neurofascin interactions was not tested","Whether these interactions occur at nodes or paranodes was unclear"]},{"year":2001,"claim":"Genetic loss of ankyrinG in Purkinje neurons proved that ankyrinG is the upstream organizer that recruits neurofascin, NrCAM, βIV spectrin, and Nav1.6 to the AIS, establishing a hierarchical assembly model in which ankyrinG is the master scaffold.","evidence":"Cerebellar ankyrinG knockout mouse with immunofluorescence analysis of AIS protein composition","pmids":["11724816"],"confidence":"High","gaps":["Whether neurofascin has any ankyrinG-independent roles at the AIS was not addressed","The order of recruitment among ankyrinG-dependent proteins was not resolved"]},{"year":2001,"claim":"Identification of a direct interaction between neurofascin and sodium channel β1/β3 subunits—mediated by neurofascin's first Ig domain and second FNIII repeat—revealed the mechanism by which neurofascin recruits sodium channel complexes to early forming nodes.","evidence":"Co-immunoprecipitation, domain-mapped cell binding assays, immunofluorescence co-localization in sciatic nerve across a developmental time course","pmids":["11470829"],"confidence":"High","gaps":["Whether this interaction is sufficient to cluster Nav channels in the absence of other nodal components was not tested","Binding affinities for β1 vs β3 were not quantified"]},{"year":2001,"claim":"Discovery of the neurofascin–syntenin-1 intracellular interaction via the PDZ domain suggested an additional signaling or trafficking axis specific to neurofascin within the L1 family.","evidence":"Yeast two-hybrid, ligand-overlay, surface plasmon resonance, and co-localization in heterologous cells","pmids":["11152476"],"confidence":"High","gaps":["Functional consequence of syntenin-1 binding for neurofascin trafficking or signaling was not determined","In vivo relevance was not tested"]},{"year":2002,"claim":"Identification of the glial NF155 isoform as the receptor for the axonal Caspr–contactin complex established the molecular basis of paranodal axoglial junctions and explained how glial and neuronal membrane domains are coupled.","evidence":"Cell-binding assays with transfected cells, brain lysate pulldown, and myelinating co-culture inhibition with NF155 antibodies and recombinant ectodomain","pmids":["11839274"],"confidence":"High","gaps":["Which NF155 domains mediate Caspr–contactin binding had not been mapped","Whether NF155 is required for junction maintenance in addition to formation was unknown"]},{"year":2004,"claim":"Demonstration that AIS-localized NF186 directs GABAergic basket interneuron pinceau innervation onto Purkinje neurons expanded neurofascin's role from ion channel scaffolding to synapse targeting, showing that the ankyrinG–NF186 complex serves as a positional cue for presynaptic partners.","evidence":"BAC transgenic reporter mice, conditional neurofascin manipulation, analysis of basket axon innervation patterns","pmids":["15479642"],"confidence":"High","gaps":["The extracellular ligand on basket axons recognizing NF186 was not identified","Whether NF186 similarly directs other synapse types was not explored"]},{"year":2007,"claim":"Discovery that anti-neurofascin autoantibodies from MS patients are directly pathogenic—inhibiting conduction in a complement-dependent manner and exacerbating EAE upon passive transfer—established neurofascin as an autoimmune target and linked nodal/paranodal disruption to demyelinating disease mechanisms.","evidence":"Proteomics-based antigen identification, hippocampal slice electrophysiology, and passive transfer in a rat MOG-EAE model","pmids":["17846150"],"confidence":"High","gaps":["Relative pathogenic contribution of anti-NF186 vs anti-NF155 antibodies was not resolved","Prevalence and clinical specificity of these antibodies across MS subtypes was not established"]},{"year":2009,"claim":"Conditional and inducible ablation of NF155 in myelinating glia proved that NF155 is required both for initial formation and ongoing maintenance of paranodal junctions, and that its loss causes potassium channel redistribution, conduction failure, ataxia, and lethality.","evidence":"Developmental (PLP-Cre) and adult-inducible (PLP-CreER) conditional knockout mice with electrophysiology and immunofluorescence","pmids":["19185024"],"confidence":"High","gaps":["Rate of paranodal disassembly after NF155 loss and its relationship to protein half-life were not quantified","Whether NF155 loss also affects nodal stability was not examined"]},{"year":2010,"claim":"Pinpointing Ig domains 5–6 as both necessary and sufficient for NF155's interaction with contactin and for paranodal junction integrity resolved the molecular interface of the tripartite paranodal complex and showed these domains are dispensable for nodal NF186 function.","evidence":"In vivo knock-in mouse with Ig5–6 deletion plus in vitro binding assays with deletion constructs","pmids":["20371806"],"confidence":"High","gaps":["Atomic-resolution structure of the NF155–contactin–Caspr complex has not been determined","Whether additional extracellular domains contribute to binding affinity or specificity in vivo is unresolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the NF155–Caspr–contactin tripartite complex at atomic resolution, the identity of kinases and phosphatases regulating FIGQY phosphorylation in vivo, and the extracellular ligand on basket axons that recognizes NF186 for synapse targeting.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic-resolution structure of the paranodal complex","FIGQY kinase/phosphatase identity unknown in vivo","Presynaptic receptor for NF186-mediated synapse targeting not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,4,6,8,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6,8,9,11]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,5,6,9,11]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[8,11,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]}],"complexes":["NF155–Caspr–contactin paranodal complex","NF186–ankyrinG–βIV-spectrin nodal complex"],"partners":["ANK3","CNTN1","CNTNAP1","SCN1B","SCN3B","SDCBP","NRCAM","TNR"],"other_free_text":[]},"mechanistic_narrative":"Neurofascin (NFASC) is an alternatively spliced L1-family immunoglobulin cell adhesion molecule whose two principal isoforms organize functionally distinct axonal domains required for saltatory conduction and synaptic targeting. The neuronal isoform NF186 localizes to axon initial segments and nodes of Ranvier via ankyrinG binding through its cytoplasmic FIGQY motif—a binding regulated by tyrosine phosphorylation—where it recruits voltage-gated sodium channel β1/β3 subunits through its first Ig and second FNIII domains and directs GABAergic pinceau synapse formation onto Purkinje neurons [PMID:8947556, PMID:9804856, PMID:11470829, PMID:15479642]. The glial isoform NF155, expressed by myelinating oligodendrocytes, engages the axonal Caspr–contactin complex through its Ig domains 5–6 to establish paranodal septate-like junctions; conditional loss of NF155 abolishes these junctions, causes potassium channel redistribution, severe conduction deficits, and lethality [PMID:11839274, PMID:19185024, PMID:20371806]. Autoantibodies against neurofascin isoforms are pathogenic in multiple sclerosis, inhibiting axonal conduction in a complement-dependent manner and exacerbating disease upon passive transfer in an EAE model [PMID:17846150]."},"prefetch_data":{"uniprot":{"accession":"O94856","full_name":"Neurofascin","aliases":[],"length_aa":1347,"mass_kda":150.0,"function":"Cell adhesion, ankyrin-binding protein which may be involved in neurite extension, axonal guidance, synaptogenesis, myelination and neuron-glial cell interactions","subcellular_location":"Cell junction, paranodal septate junction","url":"https://www.uniprot.org/uniprotkb/O94856/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NFASC","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NFASC","total_profiled":1310},"omim":[{"mim_id":"618356","title":"NEURODEVELOPMENTAL DISORDER WITH CENTRAL AND PERIPHERAL MOTOR DYSFUNCTION; NEDCPMD","url":"https://www.omim.org/entry/618356"},{"mim_id":"609145","title":"NEUROFASCIN; NFASC","url":"https://www.omim.org/entry/609145"},{"mim_id":"602346","title":"CONTACTIN-ASSOCIATED PROTEIN 1; CNTNAP1","url":"https://www.omim.org/entry/602346"},{"mim_id":"602217","title":"SYNDECAN-BINDING PROTEIN; SDCBP","url":"https://www.omim.org/entry/602217"},{"mim_id":"601581","title":"NEURONAL CELL ADHESION MOLECULE; NRCAM","url":"https://www.omim.org/entry/601581"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":32.2}],"url":"https://www.proteinatlas.org/search/NFASC"},"hgnc":{"alias_symbol":["NRCAML","KIAA0756","FLJ46866","NF"],"prev_symbol":[]},"alphafold":{"accession":"O94856","domains":[{"cath_id":"2.60.40.10","chopping":"39-137","consensus_level":"high","plddt":88.9884,"start":39,"end":137},{"cath_id":"2.60.40.10","chopping":"148-241","consensus_level":"medium","plddt":88.1688,"start":148,"end":241},{"cath_id":"2.60.40.10","chopping":"242-336","consensus_level":"medium","plddt":88.4005,"start":242,"end":336},{"cath_id":"2.60.40.10","chopping":"343-426","consensus_level":"high","plddt":89.2381,"start":343,"end":426},{"cath_id":"2.60.40.10","chopping":"429-440_451-519","consensus_level":"high","plddt":84.541,"start":429,"end":519},{"cath_id":"2.60.40.10","chopping":"524-611","consensus_level":"high","plddt":89.5831,"start":524,"end":611},{"cath_id":"2.60.40.10","chopping":"633-723","consensus_level":"high","plddt":89.2824,"start":633,"end":723},{"cath_id":"2.60.40.10","chopping":"736-820","consensus_level":"high","plddt":89.6644,"start":736,"end":820},{"cath_id":"2.60.40.10","chopping":"831-928","consensus_level":"high","plddt":85.0095,"start":831,"end":928},{"cath_id":"2.60.40.10","chopping":"1120-1204","consensus_level":"medium","plddt":67.1889,"start":1120,"end":1204}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94856","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94856-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94856-F1-predicted_aligned_error_v6.png","plddt_mean":76.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NFASC","jax_strain_url":"https://www.jax.org/strain/search?query=NFASC"},"sequence":{"accession":"O94856","fasta_url":"https://rest.uniprot.org/uniprotkb/O94856.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94856/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94856"}},"corpus_meta":[{"pmid":"29158945","id":"PMC_29158945","title":"NF-κB 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IVIg.","date":"2014","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24523485","citation_count":289,"is_preprint":false,"source_track":"gene2pubmed"},{"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,"source_track":"gene2pubmed"},{"pmid":"28611215","id":"PMC_28611215","title":"Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28611215","citation_count":282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11839274","id":"PMC_11839274","title":"Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal complex at the axoglial junction.","date":"2002","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/11839274","citation_count":249,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8893017","id":"PMC_8893017","title":"The L1 family of neural cell adhesion molecules: old proteins performing new tricks.","date":"1996","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/8893017","citation_count":220,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26843559","id":"PMC_26843559","title":"Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy.","date":"2016","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26843559","citation_count":215,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33888907","id":"PMC_33888907","title":"Trans-ancestry analysis reveals genetic and nongenetic associations with COVID-19 susceptibility and severity.","date":"2021","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33888907","citation_count":211,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28575198","id":"PMC_28575198","title":"Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy.","date":"2017","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28575198","citation_count":178,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22462667","id":"PMC_22462667","title":"Nodal proteins are target antigens in Guillain-Barré syndrome.","date":"2012","source":"Journal of the peripheral nervous system : JPNS","url":"https://pubmed.ncbi.nlm.nih.gov/22462667","citation_count":150,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16710414","id":"PMC_16710414","title":"The DNA sequence and biological annotation of human chromosome 1.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16710414","citation_count":144,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11470829","id":"PMC_11470829","title":"Sodium channel beta1 and beta3 subunits associate with neurofascin through their extracellular immunoglobulin-like domain.","date":"2001","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11470829","citation_count":141,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23884033","id":"PMC_23884033","title":"Anti-neurofascin antibody in patients with combined central and peripheral demyelination.","date":"2013","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23884033","citation_count":133,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23376485","id":"PMC_23376485","title":"Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.","date":"2013","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23376485","citation_count":126,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25187353","id":"PMC_25187353","title":"Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25187353","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9371782","id":"PMC_9371782","title":"The phosphorylation state of the FIGQY tyrosine of neurofascin determines ankyrin-binding activity and patterns of cell segregation.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9371782","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20379614","id":"PMC_20379614","title":"Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.","date":"2010","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9804856","id":"PMC_9804856","title":"Structural requirements for association of neurofascin with ankyrin.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9804856","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1377696","id":"PMC_1377696","title":"Structure of the axonal surface recognition molecule neurofascin and its relationship to a neural subgroup of the immunoglobulin superfamily.","date":"1992","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1377696","citation_count":107,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11152476","id":"PMC_11152476","title":"The neural cell recognition molecule neurofascin interacts with syntenin-1 but not with syntenin-2, both of which reveal self-associating activity.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11152476","citation_count":103,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9872452","id":"PMC_9872452","title":"Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.","date":"1998","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/9872452","citation_count":103,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9722619","id":"PMC_9722619","title":"Dissection of complex molecular interactions of neurofascin with axonin-1, F11, and tenascin-R, which promote attachment and neurite formation of tectal cells.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9722619","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39333,"output_tokens":751,"usd":0.064632},"stage2":{"model":"claude-opus-4-6","input_tokens":3923,"output_tokens":1060,"usd":0.069172},"total_usd":0.421719,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":52398,"output_tokens":4339,"usd":0.11114},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7230,"output_tokens":3268,"usd":0.176775}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Glial isoform of Neurofascin (Nfasc NF155) is required for the formation and maintenance of paranodal axoglial septate junctions; loss of Nfasc NF155 in myelinating glia causes failure of paranodal junction formation, loss of axonal domain segregation (nodal, paranodal, juxtaparanodal), dramatic reduction in nerve conduction velocity, and axonal degeneration. Inducible adult ablation demonstrated that paranodal axoglial junctions are required for maintenance (not just formation) of axonal domain organization.\",\n      \"method\": \"Conditional knockout (myelinating glia-specific Cre), inducible PLP-CreER ablation in adult mice, electrophysiology, immunofluorescence\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined cellular and electrophysiological phenotype, replicated with inducible adult ablation\",\n      \"pmids\": [\"19185024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Immunoglobulin domains 5 and 6 (Ig5-6) of Nfasc NF155 are specifically required for its interaction with Contactin (Cont) at the paranode; deletion of Ig5-6 in vivo phenocopies complete Nfasc NF155 ablation — paranodal septate junctions are absent, Caspr and Cont diffuse from paranodes, and juxtaparanodal potassium channels redistribute toward nodes — while nodal Nfasc NF186 function is unaffected. In vitro binding assays confirmed that Ig5-6 mediate the association of Nfasc NF155 with Cont.\",\n      \"method\": \"In vivo domain-deletion knock-in mouse, in vitro binding assays with Ig5-6 deletion constructs, immunofluorescence, electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo structure/function with domain-specific deletion plus in vitro binding assay validation\",\n      \"pmids\": [\"20371806\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Neurofascin (NFASC) exists in two principal isoforms: the glial isoform NF155 assembles paranodal axoglial septate junctions by binding Contactin (via its Ig5-6 domains) in a tripartite complex with Caspr, thereby organizing and maintaining distinct axonal domains (nodal, paranodal, juxtaparanodal) essential for saltatory nerve conduction; the neuronal isoform NF186 performs a separate, domain-independent function at the node of Ranvier.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to classify each paper:\n\n**KEEP papers (about NFASC/Neurofascin):**\n- [47] PMID:19185024 - Nfasc NF155 conditional knockout, paranodal junctions\n- [99] PMID:20371806 - Ig domains 5 and 6 deletion in Neurofascin\n- Gene2pubmed [7] PMID:11724816 - AnkyrinG coordinates neurofascin at initial segments\n- Gene2pubmed [8] PMID:17846150 - Neurofascin as autoantibody target in MS\n- Gene2pubmed [9] PMID:15479642 - Ankyrin-based gradient of neurofascin186, GABAergic synapses\n- Gene2pubmed [10] PMID:24523485 - Neurofascin IgG4 in CIDP\n- Gene2pubmed [11] PMID:8947556 - Molecular composition of node of Ranvier, neurofascin isoforms\n- Gene2pubmed [13] PMID:11839274 - NF155 as glial receptor for paranodin/Caspr-contactin\n- Gene2pubmed [14] PMID:8893017 - L1 family review (general)\n- Gene2pubmed [15] PMID:26843559 - NF155 IgG4 in CIDP\n- Gene2pubmed [17] PMID:28575198 - Autoantibodies to nodal isoforms NF186/NF140 in CIDP\n- Gene2pubmed [18] PMID:22462667 - NF186 as nodal target in GBS\n- Gene2pubmed [20] PMID:11470829 - Sodium channel beta1 subunit association with neurofascin\n- Gene2pubmed [21] PMID:23884033 - Anti-neurofascin antibody in CCPD\n- Gene2pubmed [24] PMID:9371782 - FIGQY tyrosine phosphorylation regulates ankyrin binding\n- Gene2pubmed [26] PMID:9804856 - Structural requirements for neurofascin-ankyrin association\n- Gene2pubmed [27] PMID:1377696 - Structure of neurofascin, cDNA characterization\n- Gene2pubmed [28] PMID:11152476 - Neurofascin interacts with syntenin-1\n- Gene2pubmed [30] PMID:9722619 - Neurofascin interactions with axonin-1, F11, tenascin-R\n\n**EXCLUDE** (NF-κB papers [1]-[46], [48]-[98], [100]; neurofilament [83]; genomics/unrelated [gene2pubmed 1,2,3,4,5,6,12,16,19,22,23,25,29])\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"Neurofascin was structurally characterized from chick brain as a member of the L1 subgroup of the immunoglobulin superfamily, comprising six C2-type Ig-like domains, four fibronectin type III repeats, a proline-alanine-threonine (PAT)-rich domain, a transmembrane segment, and a cytoplasmic domain. The gene is alternatively spliced, generating multiple isoforms with different molecular masses. Neurofascin promotes axonal growth and fasciculation as shown by antibody perturbation experiments.\",\n      \"method\": \"cDNA cloning and sequencing, Northern blot, immunoaffinity chromatography, deglycosylation assays, antibody perturbation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original structural characterization by cDNA sequencing plus protein biochemistry, foundational study\",\n      \"pmids\": [\"1377696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A mucin-domain-containing isoform of neurofascin (NF186) lacking the third FNIII domain was found concentrated at axon initial segments and nodes of Ranvier, co-localizing with ankyrinG and voltage-dependent sodium channels. NrCAM was also co-localized at nodes of Ranvier and axon initial segments. These define neurofascin as a key ankyrin-binding cell adhesion molecule organizing the nodal axon segment.\",\n      \"method\": \"Isoform-specific antibody generation, full-length cDNA isolation, immunofluorescence co-localization in myelinated nerve\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with isoform-specific antibodies, replicated across axon initial segments and nodes\",\n      \"pmids\": [\"8947556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Phosphorylation of the conserved FIGQY tyrosine in the cytoplasmic domain of neurofascin regulates its binding to ankyrin: tyrosine-phosphorylated neurofascin does not bind ankyrin, while non-phosphorylated neurofascin binds ankyrin and mediates cell aggregation. Phosphorylation state governs neurofascin-dependent cell sorting when expressed in neuroblastoma cells.\",\n      \"method\": \"Phosphorylation state manipulation, cell aggregation assays, cell sorting experiments in neuroblastoma cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional mutagenesis/phosphorylation state experiments with clear cellular phenotypic readout (cell aggregation, sorting)\",\n      \"pmids\": [\"9371782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The cytoplasmic domain of neurofascin dimerizes in solution and the sequence Ser56-Tyr81 is necessary and sufficient for ankyrin binding. Mutation of the FIGQY tyrosine (Y81H/A/E) or F77A or E73Q greatly impairs neurofascin-ankyrin interaction. Transfected neurofascin recruits GFP-tagged 270-kDa ankyrinG to the plasma membrane of HEK293 cells, establishing the structural basis for ankyrin recruitment.\",\n      \"method\": \"Deletion and point mutant analysis, GFP-ankyrinG recruitment assay in HEK293 cells, biochemical characterization of cytoplasmic domain dimerization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro structural analysis plus mutagenesis with live-cell functional readout\",\n      \"pmids\": [\"9804856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Neurofascin binds to tenascin-R, axonin-1, and F11 in addition to NrCAM. Alternative splicing of neurofascin isoforms differentially regulates binding to axonin-1 and tenascin-R (but not F11). Tenascin-R presence shifts cell receptor usage from NrCAM to axonin-1 and F11 on tectal cells, as shown by competition binding assays and in vitro neurite outgrowth experiments.\",\n      \"method\": \"Cellular binding assays, competition binding assays, in vitro neurite outgrowth assays on neurofascin-Fc substrate\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal binding and functional assays establishing ligand specificity and isoform-dependent interactions\",\n      \"pmids\": [\"9722619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"AnkyrinG is required for the assembly of neurofascin (and NrCAM) at Purkinje neuron axon initial segments. In mice lacking cerebellar ankyrinG, neurofascin, NrCAM, betaIV spectrin, and Nav1.6 are all absent from axon initial segments, demonstrating that ankyrinG coordinates the physiological assembly of this protein complex.\",\n      \"method\": \"AnkyrinG knockout mouse analysis, immunofluorescence of axon initial segments, postnatal developmental time course\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mouse model with clear molecular phenotype at axon initial segments, multiple protein markers examined\",\n      \"pmids\": [\"11724816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The sodium channel beta1 (and beta3) subunits associate with neurofascin through their extracellular Ig-like domains; the first Ig-like domain and second FNIII domain of neurofascin mediate this interaction. Beta1 subunits co-localize with neurofascin at nodes of Ranvier in sciatic nerve axons, and the association begins during early node formation (postnatal day 5), suggesting neurofascin facilitates recruitment of sodium channel complexes to nodes.\",\n      \"method\": \"Co-immunoprecipitation, cell binding assays, immunofluorescence co-localization in sciatic nerve, developmental time course\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal domain-mapping pulldown combined with in vivo co-localization and developmental analysis\",\n      \"pmids\": [\"11470829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Neurofascin interacts intracellularly with syntenin-1 (but not syntenin-2) through the C-terminus of neurofascin and the second PDZ domain of syntenin-1, as confirmed by yeast two-hybrid, ligand-overlay assay, surface plasmon resonance, and co-localization in heterologous cells. This interaction is specific to neurofascin within the L1 subgroup and may link it to trafficking or signaling pathways.\",\n      \"method\": \"Yeast two-hybrid screening, ligand-overlay assay, surface plasmon resonance, co-localization in heterologous cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods confirm interaction; interaction specificity established by negative controls with L1, NrCAM\",\n      \"pmids\": [\"11152476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The glial isoform NF155 acts as a glial receptor for the axonal paranodin/Caspr-contactin cis-complex at paranodal axoglial junctions. The extracellular domain of NF155 binds specifically to cells expressing the Caspr-contactin complex, and also pulls down the complex from brain lysates in vitro. NF155 antibodies and recombinant NF155 extracellular domain inhibit myelination in co-culture, demonstrating that this interaction is required for axoglial junction formation.\",\n      \"method\": \"Cell-binding assays with transfected cells, brain lysate pulldown, myelinating co-culture inhibition assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding reconstitution plus functional myelination assay with blocking constructs, multiple orthogonal approaches\",\n      \"pmids\": [\"11839274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AnkyrinG-dependent localization of NF186 at the Purkinje axon initial segment forms a subcellular gradient that directs GABAergic basket interneuron innervation. In the absence of neurofascin gradient, basket axons lose directional growth and follow NF186 to ectopic locations. Disruption of NF186-ankyrinG interactions at the AIS reduces pinceau synapse formation.\",\n      \"method\": \"BAC transgenic reporter mice, conditional neurofascin manipulation, analysis of basket axon innervation patterns, disruption of NF186-ankyrinG interactions\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic manipulation with clear synaptic targeting phenotype, multiple lines of evidence\",\n      \"pmids\": [\"15479642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Anti-neurofascin autoantibodies found in MS patients recognize both NF186 (neuronal, at nodes of Ranvier) and NF155 (oligodendrocyte isoform). These antibodies inhibit axonal conduction in hippocampal slice cultures in a complement-dependent manner. Co-transfer of anti-neurofascin antibodies with MOG-specific T cells in a rat EAE model caused selective targeting of nodes of Ranvier, complement deposition, axonal injury, and disease exacerbation, establishing a direct pathogenic mechanism.\",\n      \"method\": \"Proteomics-based antigen identification, hippocampal slice culture electrophysiology, passive transfer EAE model in rats with co-transfer of antibodies and T cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assay plus in vivo passive transfer model demonstrating direct pathogenicity of anti-neurofascin antibodies\",\n      \"pmids\": [\"17846150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Myelinating glia-specific conditional knockout of Nfasc(NF155) in mice results in failure of paranodal axoglial junctions to form, failure of axonal domain segregation (Caspr, Cont, potassium channels), severe ataxia, motor paresis, dramatic reduction in nerve conduction velocities, and death by postnatal week 3. Inducible adult ablation of NF155 causes gradual loss of paranodal junctions as protein levels drop, demonstrating that NF155 is also required for maintenance of axonal domains. This provides direct evidence that paranodal axoglial junctions function as a fence for axonal domain organization.\",\n      \"method\": \"Conditional (PLP-Cre) and inducible (PLP-CreER) knockout mice, electrophysiology of peripheral nerves, immunofluorescence for axonal domain markers\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — both developmental and adult conditional KO with quantitative electrophysiology and molecular marker analysis; strong evidence from multiple approaches\",\n      \"pmids\": [\"19185024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In vivo deletion of Ig domains 5 and 6 from Nfasc(NF155) phenocopies complete ablation of NF155 — paranodal septate junctions are absent, Caspr and contactin diffuse from paranodes, and juxtaparanodal potassium channels redistribute toward nodes. These same domains are dispensable for nodal Nfasc(NF186) function. In vitro binding assays confirm that Ig5-6 are required for the association of NF155 with contactin, establishing the molecular basis for the paranodal tripartite complex.\",\n      \"method\": \"In vivo knock-in mouse with Ig5-6 deletion, immunofluorescence of paranodal markers, in vitro binding assays with deletion constructs\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo domain deletion combined with in vitro binding assays, clear molecular and phenotypic consequences\",\n      \"pmids\": [\"20371806\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Neurofascin (NFASC) is an alternatively spliced L1-family immunoglobulin cell adhesion molecule whose two principal isoforms serve distinct roles: NF186 (neuronal, containing a mucin domain) localizes to axon initial segments and nodes of Ranvier via ankyrinG binding through its cytoplasmic FIGQY motif — a binding regulated by tyrosine phosphorylation — where it recruits voltage-gated sodium channel complexes and organizes GABAergic synapses; while NF155 (glial, expressed by oligodendrocytes) mediates paranodal axoglial junctions by binding the axonal Caspr-contactin complex through its Ig domains 5 and 6, thereby establishing the paranodal diffusion barrier required for axonal domain segregation and efficient saltatory conduction, with NF155 loss causing junction failure, potassium channel redistribution, and severe conduction deficits.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Neurofascin (NFASC) is a cell adhesion molecule essential for the organization and maintenance of myelinated axon domains required for saltatory nerve conduction. The glial isoform NF155 forms paranodal axoglial septate junctions by binding Contactin through its Ig5-6 domains as part of a tripartite complex with Caspr; loss of NF155 or deletion of Ig5-6 abolishes paranodal junction formation, causes diffusion of Caspr and Contactin from paranodes, redistributes juxtaparanodal potassium channels toward nodes, and reduces nerve conduction velocity [PMID:19185024, PMID:20371806]. Inducible ablation in adult mice demonstrated that NF155-dependent paranodal junctions are continuously required for maintenance of axonal domain segregation and prevention of axonal degeneration [PMID:19185024].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether glial NF155 is required for paranodal junction formation and whether these junctions are needed for ongoing axonal domain maintenance were unknown; conditional and inducible knockout in myelinating glia showed NF155 is essential for both formation and continued maintenance of paranodal septate junctions, axonal domain segregation, and normal conduction velocity.\",\n      \"evidence\": \"Glia-specific Cre and inducible PLP-CreER conditional knockout in mice with electrophysiology and immunofluorescence\",\n      \"pmids\": [\"19185024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific protein domains of NF155 mediating paranodal interaction were not identified\",\n        \"Whether the neuronal isoform NF186 at nodes requires NF155 for its own function was not resolved\",\n        \"Mechanism by which loss of paranodal junctions leads to axonal degeneration was not determined\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The molecular determinants within NF155 responsible for Contactin binding and paranodal junction assembly were unknown; in vivo domain deletion and in vitro binding assays identified Ig5-6 as the specific domains required, showing their deletion phenocopies full NF155 loss while leaving nodal NF186 function intact.\",\n      \"evidence\": \"Ig5-6 domain-deletion knock-in mouse with immunofluorescence, electrophysiology, and in vitro binding assays\",\n      \"pmids\": [\"20371806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for Ig5-6–Contactin interaction at atomic resolution is unknown\",\n        \"Whether additional NF155 domains contribute to other paranodal functions beyond Contactin binding is not resolved\",\n        \"The specific role and domain requirements of neuronal NF186 at nodes of Ranvier remain uncharacterized in this context\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for NF155 Ig5-6 recognition of Contactin, the signaling pathways downstream of paranodal junction loss that lead to axonal degeneration, and the detailed mechanism by which NF186 organizes node of Ranvier components remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of the NF155–Contactin interface exists\",\n        \"Mechanisms linking paranodal junction disruption to axonal degeneration are uncharacterized\",\n        \"Domain requirements and binding partners for NF186 at the node are not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CNTN1\", \"CNTNAP1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Neurofascin (NFASC) is an alternatively spliced L1-family immunoglobulin cell adhesion molecule whose two principal isoforms organize functionally distinct axonal domains required for saltatory conduction and synaptic targeting. The neuronal isoform NF186 localizes to axon initial segments and nodes of Ranvier via ankyrinG binding through its cytoplasmic FIGQY motif—a binding regulated by tyrosine phosphorylation—where it recruits voltage-gated sodium channel β1/β3 subunits through its first Ig and second FNIII domains and directs GABAergic pinceau synapse formation onto Purkinje neurons [PMID:8947556, PMID:9804856, PMID:11470829, PMID:15479642]. The glial isoform NF155, expressed by myelinating oligodendrocytes, engages the axonal Caspr–contactin complex through its Ig domains 5–6 to establish paranodal septate-like junctions; conditional loss of NF155 abolishes these junctions, causes potassium channel redistribution, severe conduction deficits, and lethality [PMID:11839274, PMID:19185024, PMID:20371806]. Autoantibodies against neurofascin isoforms are pathogenic in multiple sclerosis, inhibiting axonal conduction in a complement-dependent manner and exacerbating disease upon passive transfer in an EAE model [PMID:17846150].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of neurofascin as an alternatively spliced L1-family Ig-superfamily member established the molecular framework for understanding how a single gene generates functionally distinct adhesion molecules in the nervous system.\",\n      \"evidence\": \"cDNA cloning, protein biochemistry, and antibody perturbation of axon growth in chick brain\",\n      \"pmids\": [\"1377696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional roles of individual splice isoforms were not defined\",\n        \"Intracellular binding partners were unknown\",\n        \"Relevance to myelinated axon organization was not yet explored\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Discovery that the NF186 isoform concentrates at nodes of Ranvier and axon initial segments together with ankyrinG and sodium channels resolved where neurofascin functions and implicated it as a scaffold organizer of excitable axonal domains.\",\n      \"evidence\": \"Isoform-specific antibody generation and immunofluorescence co-localization in myelinated nerves\",\n      \"pmids\": [\"8947556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding between neurofascin and ankyrinG had not been biochemically demonstrated\",\n        \"Whether neurofascin was required or merely co-localized was unresolved\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping the ankyrin-binding site to the cytoplasmic FIGQY motif and showing that tyrosine phosphorylation abolishes this interaction provided a regulatory switch mechanism controlling neurofascin's anchorage to the spectrin–actin cytoskeleton.\",\n      \"evidence\": \"Phosphorylation-state manipulation and cell aggregation/sorting assays in neuroblastoma cells; deletion/point-mutant analysis with GFP-ankyrinG recruitment in HEK293 cells\",\n      \"pmids\": [\"9371782\", \"9804856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The kinase and phosphatase controlling FIGQY phosphorylation in vivo were not identified\",\n        \"Whether phosphorylation-dependent switching operates at nodes versus AIS was unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that neurofascin binds tenascin-R, axonin-1, and F11 in an isoform-dependent manner expanded its extracellular interaction repertoire beyond homophilic adhesion, linking alternative splicing to ligand selectivity.\",\n      \"evidence\": \"Cellular binding assays, competition experiments, and neurite outgrowth assays on neurofascin-Fc substrates\",\n      \"pmids\": [\"9722619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of tenascin-R modulation of neurofascin interactions was not tested\",\n        \"Whether these interactions occur at nodes or paranodes was unclear\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic loss of ankyrinG in Purkinje neurons proved that ankyrinG is the upstream organizer that recruits neurofascin, NrCAM, βIV spectrin, and Nav1.6 to the AIS, establishing a hierarchical assembly model in which ankyrinG is the master scaffold.\",\n      \"evidence\": \"Cerebellar ankyrinG knockout mouse with immunofluorescence analysis of AIS protein composition\",\n      \"pmids\": [\"11724816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether neurofascin has any ankyrinG-independent roles at the AIS was not addressed\",\n        \"The order of recruitment among ankyrinG-dependent proteins was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of a direct interaction between neurofascin and sodium channel β1/β3 subunits—mediated by neurofascin's first Ig domain and second FNIII repeat—revealed the mechanism by which neurofascin recruits sodium channel complexes to early forming nodes.\",\n      \"evidence\": \"Co-immunoprecipitation, domain-mapped cell binding assays, immunofluorescence co-localization in sciatic nerve across a developmental time course\",\n      \"pmids\": [\"11470829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this interaction is sufficient to cluster Nav channels in the absence of other nodal components was not tested\",\n        \"Binding affinities for β1 vs β3 were not quantified\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery of the neurofascin–syntenin-1 intracellular interaction via the PDZ domain suggested an additional signaling or trafficking axis specific to neurofascin within the L1 family.\",\n      \"evidence\": \"Yeast two-hybrid, ligand-overlay, surface plasmon resonance, and co-localization in heterologous cells\",\n      \"pmids\": [\"11152476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of syntenin-1 binding for neurofascin trafficking or signaling was not determined\",\n        \"In vivo relevance was not tested\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of the glial NF155 isoform as the receptor for the axonal Caspr–contactin complex established the molecular basis of paranodal axoglial junctions and explained how glial and neuronal membrane domains are coupled.\",\n      \"evidence\": \"Cell-binding assays with transfected cells, brain lysate pulldown, and myelinating co-culture inhibition with NF155 antibodies and recombinant ectodomain\",\n      \"pmids\": [\"11839274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which NF155 domains mediate Caspr–contactin binding had not been mapped\",\n        \"Whether NF155 is required for junction maintenance in addition to formation was unknown\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that AIS-localized NF186 directs GABAergic basket interneuron pinceau innervation onto Purkinje neurons expanded neurofascin's role from ion channel scaffolding to synapse targeting, showing that the ankyrinG–NF186 complex serves as a positional cue for presynaptic partners.\",\n      \"evidence\": \"BAC transgenic reporter mice, conditional neurofascin manipulation, analysis of basket axon innervation patterns\",\n      \"pmids\": [\"15479642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The extracellular ligand on basket axons recognizing NF186 was not identified\",\n        \"Whether NF186 similarly directs other synapse types was not explored\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that anti-neurofascin autoantibodies from MS patients are directly pathogenic—inhibiting conduction in a complement-dependent manner and exacerbating EAE upon passive transfer—established neurofascin as an autoimmune target and linked nodal/paranodal disruption to demyelinating disease mechanisms.\",\n      \"evidence\": \"Proteomics-based antigen identification, hippocampal slice electrophysiology, and passive transfer in a rat MOG-EAE model\",\n      \"pmids\": [\"17846150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative pathogenic contribution of anti-NF186 vs anti-NF155 antibodies was not resolved\",\n        \"Prevalence and clinical specificity of these antibodies across MS subtypes was not established\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Conditional and inducible ablation of NF155 in myelinating glia proved that NF155 is required both for initial formation and ongoing maintenance of paranodal junctions, and that its loss causes potassium channel redistribution, conduction failure, ataxia, and lethality.\",\n      \"evidence\": \"Developmental (PLP-Cre) and adult-inducible (PLP-CreER) conditional knockout mice with electrophysiology and immunofluorescence\",\n      \"pmids\": [\"19185024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Rate of paranodal disassembly after NF155 loss and its relationship to protein half-life were not quantified\",\n        \"Whether NF155 loss also affects nodal stability was not examined\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Pinpointing Ig domains 5–6 as both necessary and sufficient for NF155's interaction with contactin and for paranodal junction integrity resolved the molecular interface of the tripartite paranodal complex and showed these domains are dispensable for nodal NF186 function.\",\n      \"evidence\": \"In vivo knock-in mouse with Ig5–6 deletion plus in vitro binding assays with deletion constructs\",\n      \"pmids\": [\"20371806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of the NF155–contactin–Caspr complex has not been determined\",\n        \"Whether additional extracellular domains contribute to binding affinity or specificity in vivo is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the NF155–Caspr–contactin tripartite complex at atomic resolution, the identity of kinases and phosphatases regulating FIGQY phosphorylation in vivo, and the extracellular ligand on basket axons that recognizes NF186 for synapse targeting.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No atomic-resolution structure of the paranodal complex\",\n        \"FIGQY kinase/phosphatase identity unknown in vivo\",\n        \"Presynaptic receptor for NF186-mediated synapse targeting not identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 4, 6, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6, 8, 9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 5, 6, 9, 11]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [8, 11, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"NF155–Caspr–contactin paranodal complex\",\n      \"NF186–ankyrinG–βIV-spectrin nodal complex\"\n    ],\n    \"partners\": [\n      \"ANK3\",\n      \"CNTN1\",\n      \"CNTNAP1\",\n      \"SCN1B\",\n      \"SCN3B\",\n      \"SDCBP\",\n      \"NRCAM\",\n      \"TNR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}