{"gene":"CBLN4","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2007,"finding":"Cbln2 and Cbln4 are secreted as N-linked glycoproteins when expressed in mammalian heterologous cells. All Cbln family members form not only homomeric but also heteromeric complexes with each other in vitro, and heteromer formation between Cbln1 and Cbln3 modulates each other's trafficking and secretion.","method":"Mammalian cell expression, glycoprotein secretion assays, co-immunoprecipitation, subcellular fractionation","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal biochemical characterization in heterologous cells with multiple assays (secretion, co-IP, ER/Golgi fractionation), single lab","pmids":["17331201"],"is_preprint":false},{"year":2008,"finding":"Cbln4 (but not Cbln1 or Cbln2) binds selectively to the netrin receptor DCC (deleted in colorectal cancer) in a netrin-displaceable fashion. Cbln1/Cbln4 heteromeric complexes have greatly reduced affinity for DCC but increased affinity for neurexins compared to Cbln4 alone, indicating subunit-composition-dependent receptor binding.","method":"Candidate receptor-screening binding assay, pulldown, netrin displacement competition assay, generation of Cbln4-null mice","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with competition controls and genetic KO validation, single lab with multiple orthogonal methods","pmids":["22220752"],"is_preprint":false},{"year":2011,"finding":"Cbln4 does not specifically bind to neurexin α and β isoforms carrying the splice site 4 insert [NRXs(S4+)] and does not induce synaptogenesis in cerebellar, hippocampal, or cortical neurons in vitro, unlike Cbln1 and Cbln2.","method":"In vitro synaptogenesis assay, binding assays in cultured neurons","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative binding and synaptogenesis result replicated by two independent labs (PMID 21410790 and 21356198) using multiple neuronal culture systems","pmids":["21410790","21356198"],"is_preprint":false},{"year":2011,"finding":"Cbln4 shows only weak interactions with NRXN1α and β-NRXNs as measured by surface plasmon resonance, with binding affinity much lower than Cbln1 or Cbln2, and Cbln4 exhibited little synaptogenic activity in cortical neuron cultures.","method":"Surface plasmon resonance, in vitro synaptogenesis assay with cortical neurons","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding affinity measured by SPR (a rigorous biophysical method), corroborated by functional synaptogenesis assay, replicated across labs","pmids":["21356198"],"is_preprint":false},{"year":2014,"finding":"CBLN4 and Netrin-1 are identified as extracellular binding partners of DCC using protein microarray screens. CBLN4 binds to DCC at an overlapping site within membrane-proximal fibronectin domains FN4-6, with Netrin-1 competing with CBLN4 binding and exhibiting ~5-fold higher affinity. CBLN4 also binds to DCC homolog Neogenin-1 (NEO1) with lower affinity than DCC.","method":"Extracellular protein microarray screen (>1000 proteins), immunofluorescence, radio-ligand binding competition assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative radio-ligand binding with competition assay defining binding site, supported by independent microarray discovery and orthogonal fluorescence methods","pmids":["24400119"],"is_preprint":false},{"year":2017,"finding":"Crystal structures of the C1q domain homotrimers of Cbln1 and Cbln4 were solved at 2.2 Å and 2.3 Å resolution, respectively. Structural comparison revealed that sequence and structural divergence in loop CD accounts for the difference in GluD2 binding between Cbln1 and Cbln4. Cbln4 was shown to form a stable complex with the LNS domain of Nrxn1β, and negative-stain EM reconstruction suggested Nrxn1β binds to the N-terminal region of Cbln4 through strand β10 of the S4 insert.","method":"X-ray crystallography, negative-stain electron microscopy, surface plasmon resonance (stable complex formation)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures at near-atomic resolution with EM structural reconstruction of the complex and functional binding validation","pmids":["28877468"],"is_preprint":false},{"year":2018,"finding":"Glycosylation of Cbln4 at two N-linked sites attenuates receptor binding: the N-terminal glycosylation site masks neurexin binding, while the C1q domain glycosylation site masks GluD2 binding. Glycosylation mutants (asparagine-to-glutamine) of Cbln4 completely rescued ataxia in Cbln1-null mice in vivo, demonstrating that Cbln4 has intrinsic GluD2 binding that is masked by glycosylation.","method":"Site-directed mutagenesis of glycosylation sites, in vitro receptor binding assay, transgenic mouse rescue experiment","journal":"Brain research","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with in vitro binding assay and in vivo rescue, multiple orthogonal methods in one study","pmids":["29782851"],"is_preprint":false},{"year":2016,"finding":"Cbln4 is selectively co-expressed with a specific neurexin splice isoform (lacking the SS4 insert) in parvalbumin-positive (PV+) interneurons of the mouse hippocampus. Conditional ablation of neurexin alternative splice insertions selectively in PV+ cells results in elevated hippocampal network activity and learning impairment, placing Cbln4 in a PV-interneuron-specific neurexin signaling pathway.","method":"Conditional knockout mouse, electrophysiology, behavioral testing, in situ hybridization, alternative splicing analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with conditional KO and multiple functional readouts, single lab","pmids":["27960072"],"is_preprint":false},{"year":2018,"finding":"Constitutive Cbln4 knockout mice are viable and fertile, and single Cbln4 deletion does not produce the striatal synaptic changes seen in Cbln1-null mice. Combined Cbln1/2/4 triple KO aggravates salience-induced seizures observed in Cbln1/2 double KO, indicating Cbln4 contributes to brain function redundantly with other cerebellins. Cerebellins including Cbln4 are not required for initial synapse formation but contribute to long-term synapse maintenance.","method":"Constitutive single, double, and triple knockout mice; synapse density quantification; behavioral phenotyping (motor, seizure)","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous genetic ablation study with multiple KO combinations and anatomical/behavioral readouts, single lab","pmids":["29691328"],"is_preprint":false},{"year":2009,"finding":"Cbln4 is a direct transcriptional target of SRY and SOX9 in the developing mouse testis. Anti-SRY chromatin immunoprecipitation pulled down a region 7.5 kb upstream of the Cbln4 transcriptional start site. Reducing Sox9 expression in XY mice decreased Cbln4 expression, overexpressing Sox9 in XX mice upregulated Cbln4, and ectopic SRY expression caused ectopic Cbln4 expression.","method":"Chromatin immunoprecipitation (ChIP), transgenic mouse overexpression/knockdown, in situ expression analysis","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP identifies direct genomic binding site, replicated by multiple transgenic gain- and loss-of-function models","pmids":["19211811"],"is_preprint":false},{"year":2014,"finding":"Cbln4 plays an essential role in the formation and maintenance of inhibitory GABAergic connections in cultured hippocampal neurons. Hes1 transcription factor controls Cbln4 expression downstream of NGF. Overexpression of Cbln4 or application of recombinant Cbln4 increased GABAergic varicosities and rescued neurons from Aβ-induced death; knockdown of Cbln4 reduced GABAergic connections.","method":"Cbln4 overexpression and knockdown in cultured hippocampal neurons, recombinant protein application, immunostaining for GABAergic markers (VGAT), Aβ toxicity rescue assay","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in cultured neurons with morphological synaptic readouts, single lab","pmids":["25534236"],"is_preprint":false},{"year":2022,"finding":"Cbln4, expressed presynaptically in entorhinal cortex neurons and bound to neurexins, forms transcellular complexes with postsynaptic neogenin-1 (NEO1) in dentate gyrus granule cells. Presynaptic deletion of Cbln4 or postsynaptic deletion of NEO1 (but not DCC) in dentate granule cells blocked long-term potentiation (LTP) at entorhinal cortex→dentate gyrus synapses without affecting basal synaptic transmission, establishing a Cbln4–neogenin-1 trans-synaptic signaling pathway required for LTP competence.","method":"Conditional knockout mice (presynaptic Cbln4 deletion; postsynaptic NEO1 and DCC deletions), electrophysiology (LTP induction and basal synaptic transmission)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic epistasis with cell-type-specific conditional KOs of both presynaptic and postsynaptic components, with specific electrophysiological readout distinguishing LTP from basal transmission","pmids":["35544694"],"is_preprint":false},{"year":2024,"finding":"A GRID1 variant at a position predicted to interact with Cbln2/Cbln4 disrupts complex formation between GluD1 and Cbln2, identifying the GluD1 distal amino terminal domain as a site of interaction with Cbln4-related ligands.","method":"Site-directed mutagenesis of GRID1 variants, biochemical complex formation assay","journal":"Human molecular genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single mutagenesis experiment with Cbln2; Cbln4 interaction inferred from predicted structural similarity, not directly tested for Cbln4","pmids":["37944084"],"is_preprint":false},{"year":2024,"finding":"METTL14-mediated m6A methylation improves the stability and expression of CBLN4 mRNA. In Aβ1-42-treated SK-N-SH cells, CBLN4 and METTL14 are both downregulated; overexpression of CBLN4 relieves apoptosis, inflammation, oxidative stress, and ER stress. METTL14 was shown to regulate CBLN4 mRNA stability via m6A modification using MeRIP and dual-luciferase reporter assays.","method":"MeRIP (methylated RNA immunoprecipitation), dual-luciferase reporter assay, overexpression in SK-N-SH cells, MTT, flow cytometry, ELISA, Western blot","journal":"Journal of bioenergetics and biomembranes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and dual-luciferase reporter directly demonstrate m6A-mediated mRNA stability regulation, with functional cellular readouts, single lab","pmids":["39235700"],"is_preprint":false},{"year":2026,"finding":"Single-cell transcriptomic analysis across 17 developmental stages identifies NEOGENIN-1 as the principal postsynaptic receptor for CBLN4 during the perinatal period, mediating synapse formation between somatostatin-expressing interneurons and glutamatergic neurons in the mouse cortex.","method":"Single-cell transcriptomics across developmental stages, ligand-receptor inference","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational ligand-receptor inference from transcriptomic data; no direct binding or functional experiment reported in the abstract for this specific interaction","pmids":["41565644"],"is_preprint":false}],"current_model":"CBLN4 is a secreted N-linked glycoprotein member of the C1q/cerebellin family that forms homomeric and heteromeric complexes with other cerebellins; it binds selectively to DCC and neogenin-1 (not neurexins/GluD2 under normal glycosylation) and acts as a trans-synaptic organizer—presynaptically anchored via neurexins and interacting postsynaptically with neogenin-1 to confer LTP competence at entorhinal cortex→dentate gyrus synapses, promotes GABAergic synapse formation in hippocampal neurons, is transcriptionally regulated by SRY/SOX9 in the testis and by Hes1 in neurons, and its mRNA stability is controlled by METTL14-mediated m6A methylation; glycosylation at two N-linked sites attenuates its intrinsic GluD2 and neurexin binding."},"narrative":{"mechanistic_narrative":"CBLN4 is a secreted N-linked glycoprotein of the C1q/cerebellin family that functions as a trans-synaptic organizer, contributing redundantly with other cerebellins to synapse maintenance and plasticity rather than initial synapse formation [PMID:17331201, PMID:29691328]. It is secreted as a glycoprotein and assembles into both homomeric and heteromeric complexes with other cerebellins, and complex subunit composition tunes receptor selectivity—Cbln1/Cbln4 heteromers lose affinity for DCC while gaining affinity for neurexins [PMID:17331201, PMID:22220752]. Unlike Cbln1 and Cbln2, Cbln4 binds only weakly to neurexins and is poorly synaptogenic in standard neuronal cultures [PMID:21410790, PMID:21356198], a difference explained by glycosylation: N-linked glycans at an N-terminal site and within the C1q domain mask intrinsic neurexin and GluD2 binding, respectively, and removing these glycans unmasks GluD2 binding sufficient to rescue ataxia in Cbln1-null mice [PMID:29782851]. Crystal structures of the Cbln4 C1q-domain homotrimer localize the GluD2-binding divergence to loop CD and define a stable Nrxn1β LNS-domain complex [PMID:28877468]. CBLN4 binds selectively to the netrin receptor DCC and its homolog neogenin-1 (NEO1) at membrane-proximal fibronectin domains FN4-6, in a netrin-displaceable manner [PMID:22220752, PMID:24400119]. Physiologically, presynaptic CBLN4 anchored via neurexins in entorhinal cortex neurons engages postsynaptic NEO1 (not DCC) in dentate gyrus granule cells to confer long-term potentiation competence without affecting basal transmission [PMID:35544694], and it promotes formation and maintenance of GABAergic connections in hippocampal neurons [PMID:25534236]. Cbln4 expression is directly driven by SRY/SOX9 in the developing testis [PMID:19211811] and by Hes1 downstream of NGF in neurons [PMID:25534236], and its mRNA stability is enhanced by METTL14-mediated m6A methylation [PMID:39235700].","teleology":[{"year":2007,"claim":"Established the basic biochemical nature of CBLN4 as a secreted glycoprotein capable of multimerizing with other cerebellins, raising the question of how heteromer composition shapes function.","evidence":"Mammalian heterologous expression with secretion assays, co-IP, and subcellular fractionation","pmids":["17331201"],"confidence":"Medium","gaps":["Stoichiometry and physiological prevalence of specific heteromers in vivo not defined","No receptor binding tested at this stage"]},{"year":2008,"claim":"Identified DCC as a selective CBLN4 receptor and showed that heteromer composition switches receptor preference between DCC and neurexins, linking subunit assembly to signaling output.","evidence":"Candidate receptor binding/pulldown with netrin displacement competition and Cbln4-null mice","pmids":["22220752"],"confidence":"Medium","gaps":["Binding site on DCC not mapped","Functional consequence of DCC engagement not established"]},{"year":2011,"claim":"Distinguished CBLN4 from synaptogenic cerebellins by demonstrating it binds neurexins only weakly and lacks synaptogenic activity in vitro, indicating a divergent functional role.","evidence":"Surface plasmon resonance and in vitro synaptogenesis assays in cortical, hippocampal, and cerebellar neurons across two labs","pmids":["21356198","21410790"],"confidence":"High","gaps":["Why CBLN4 is non-synaptogenic despite cerebellin homology unresolved at this stage","In vivo synaptic role untested"]},{"year":2014,"claim":"Defined the molecular CBLN4-DCC interaction surface and extended receptor repertoire to neogenin-1, establishing competitive cross-talk with netrin-1.","evidence":"Extracellular protein microarray screen plus radio-ligand binding competition mapping to FN4-6 domains","pmids":["24400119"],"confidence":"High","gaps":["Cellular/synaptic readout of the CBLN4-DCC/NEO1 interaction not yet shown","Affinity hierarchy among receptors not fully resolved"]},{"year":2017,"claim":"Provided atomic-resolution structural basis for cerebellin functional divergence, localizing GluD2-binding specificity to loop CD and visualizing the Nrxn1β complex.","evidence":"X-ray crystallography of C1q homotrimers, negative-stain EM, and SPR","pmids":["28877468"],"confidence":"High","gaps":["Structure of the receptor-bound (DCC/NEO1) complex not solved","Role of glycosylation not addressed structurally"]},{"year":2018,"claim":"Resolved why CBLN4 appears non-synaptogenic by showing N-linked glycosylation masks intrinsic neurexin and GluD2 binding, with deglycosylated CBLN4 functionally substituting for Cbln1 in vivo.","evidence":"Glycosylation-site mutagenesis, in vitro binding, and transgenic rescue of Cbln1-null ataxia","pmids":["29782851"],"confidence":"High","gaps":["Whether glycosylation is dynamically regulated in vivo unknown","Cell-type-specific glycoforms not characterized"]},{"year":2018,"claim":"Defined the in vivo significance of CBLN4 through genetic ablation, showing it acts redundantly with other cerebellins in synapse maintenance rather than initial formation.","evidence":"Single, double, and triple cerebellin knockout mice with synapse density and behavioral phenotyping","pmids":["29691328"],"confidence":"Medium","gaps":["Specific synapses uniquely dependent on Cbln4 not identified here","Molecular partner mediating maintenance not pinpointed"]},{"year":2022,"claim":"Established a defined circuit-level function by showing presynaptic CBLN4 signals to postsynaptic neogenin-1 to confer LTP competence at entorhinal cortex→dentate gyrus synapses.","evidence":"Cell-type-specific conditional KOs of presynaptic Cbln4 and postsynaptic NEO1 versus DCC with LTP and basal transmission electrophysiology","pmids":["35544694"],"confidence":"High","gaps":["Downstream NEO1 signaling underlying LTP not defined","Generalizability to other circuits untested"]},{"year":2009,"claim":"Identified CBLN4 as a direct SRY/SOX9 transcriptional target in the testis, revealing a developmental, non-neuronal regulatory context.","evidence":"Anti-SRY ChIP and transgenic gain/loss-of-function in mouse gonad","pmids":["19211811"],"confidence":"High","gaps":["Functional role of CBLN4 in testis development unknown","Downstream effectors not identified"]},{"year":2014,"claim":"Placed CBLN4 in an NGF/Hes1-controlled program promoting GABAergic connectivity and neuronal survival under amyloid stress.","evidence":"Overexpression, knockdown, and recombinant protein application in cultured hippocampal neurons with GABAergic marker staining and Aβ toxicity rescue","pmids":["25534236"],"confidence":"Medium","gaps":["In vivo validation of GABAergic role lacking","Receptor mediating GABAergic effect not specified"]},{"year":2024,"claim":"Identified a post-transcriptional control layer, with METTL14-mediated m6A methylation stabilizing CBLN4 mRNA in a neuronal stress model.","evidence":"MeRIP and dual-luciferase reporter assays with CBLN4 overexpression in Aβ-treated SK-N-SH cells","pmids":["39235700"],"confidence":"Medium","gaps":["m6A sites not mapped at nucleotide resolution","In vivo relevance to neural function untested"]},{"year":2024,"claim":"Implicated the GluD1 distal amino-terminal domain as an interaction site for Cbln4-related ligands via a disease-associated GRID1 variant.","evidence":"Site-directed mutagenesis and biochemical complex formation assay (tested directly with Cbln2)","pmids":["37944084"],"confidence":"Low","gaps":["Cbln4 interaction inferred from structural similarity, not directly tested","Functional consequence of GluD1-Cbln4 binding unknown"]},{"year":2026,"claim":"Nominated neogenin-1 as the principal perinatal postsynaptic receptor mediating CBLN4-dependent somatostatin-interneuron-to-glutamatergic synapse formation in cortex.","evidence":"Single-cell transcriptomics across developmental stages with computational ligand-receptor inference","pmids":["41565644"],"confidence":"Low","gaps":["Computational inference without direct binding or functional validation for this interaction","Cortical interneuron synapse role not experimentally confirmed"]},{"year":null,"claim":"How CBLN4 glycosylation state, heteromer composition, and receptor choice (DCC vs NEO1 vs GluD) are coordinated to specify distinct synaptic functions across brain regions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CBLN4 bound to DCC/NEO1","Downstream intracellular signaling from NEO1 unknown","Regulation of glycoform diversity in vivo undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,4,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,0]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,4]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[11,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,11]}],"complexes":[],"partners":["DCC","NEO1","NRXN1","GRID2","CBLN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NTU7","full_name":"Cerebellin-4","aliases":["Cerebellin-like glycoprotein 1"],"length_aa":201,"mass_kda":21.8,"function":"Acts as a synaptic organizer in specific subsets of neurons in the brain (By similarity). Essential for the formation and maintenance of inhibitory GABAergic synapses (By similarity). Promotes the development of dendrite-targeting inhibitory GABAergic synapses made by somatostatin-positive interneurons (By similarity). May contribute to the function of ventral medial habenula region of the brain implicated in the regulation of anxiety-related behaviors (By similarity). May play a role in CBLN3 export from the endoplasmic reticulum and secretion (By similarity)","subcellular_location":"Secreted; Synapse","url":"https://www.uniprot.org/uniprotkb/Q9NTU7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CBLN4","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/CBLN4","total_profiled":1310},"omim":[{"mim_id":"621480","title":"OTOLIN 1; OTOL1","url":"https://www.omim.org/entry/621480"},{"mim_id":"615029","title":"PRECEREBELLIN 4; CBLN4","url":"https://www.omim.org/entry/615029"},{"mim_id":"612978","title":"PRECEREBELLIN 3; CBLN3","url":"https://www.omim.org/entry/612978"},{"mim_id":"600433","title":"PRECEREBELLIN 2; CBLN2","url":"https://www.omim.org/entry/600433"},{"mim_id":"600432","title":"PRECEREBELLIN 1; CBLN1","url":"https://www.omim.org/entry/600432"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adrenal gland","ntpm":16.8},{"tissue":"brain","ntpm":15.6},{"tissue":"epididymis","ntpm":8.3}],"url":"https://www.proteinatlas.org/search/CBLN4"},"hgnc":{"alias_symbol":["dJ885A10.1"],"prev_symbol":["CBLNL1"]},"alphafold":{"accession":"Q9NTU7","domains":[{"cath_id":"2.60.120.40","chopping":"71-199","consensus_level":"medium","plddt":93.8846,"start":71,"end":199}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTU7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTU7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NTU7-F1-predicted_aligned_error_v6.png","plddt_mean":78.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CBLN4","jax_strain_url":"https://www.jax.org/strain/search?query=CBLN4"},"sequence":{"accession":"Q9NTU7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NTU7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NTU7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NTU7"}},"corpus_meta":[{"pmid":"21410790","id":"PMC_21410790","title":"Cbln 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All Cbln family members form not only homomeric but also heteromeric complexes with each other in vitro, and heteromer formation between Cbln1 and Cbln3 modulates each other's trafficking and secretion.\",\n      \"method\": \"Mammalian cell expression, glycoprotein secretion assays, co-immunoprecipitation, subcellular fractionation\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal biochemical characterization in heterologous cells with multiple assays (secretion, co-IP, ER/Golgi fractionation), single lab\",\n      \"pmids\": [\"17331201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cbln4 (but not Cbln1 or Cbln2) binds selectively to the netrin receptor DCC (deleted in colorectal cancer) in a netrin-displaceable fashion. Cbln1/Cbln4 heteromeric complexes have greatly reduced affinity for DCC but increased affinity for neurexins compared to Cbln4 alone, indicating subunit-composition-dependent receptor binding.\",\n      \"method\": \"Candidate receptor-screening binding assay, pulldown, netrin displacement competition assay, generation of Cbln4-null mice\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with competition controls and genetic KO validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22220752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cbln4 does not specifically bind to neurexin α and β isoforms carrying the splice site 4 insert [NRXs(S4+)] and does not induce synaptogenesis in cerebellar, hippocampal, or cortical neurons in vitro, unlike Cbln1 and Cbln2.\",\n      \"method\": \"In vitro synaptogenesis assay, binding assays in cultured neurons\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative binding and synaptogenesis result replicated by two independent labs (PMID 21410790 and 21356198) using multiple neuronal culture systems\",\n      \"pmids\": [\"21410790\", \"21356198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cbln4 shows only weak interactions with NRXN1α and β-NRXNs as measured by surface plasmon resonance, with binding affinity much lower than Cbln1 or Cbln2, and Cbln4 exhibited little synaptogenic activity in cortical neuron cultures.\",\n      \"method\": \"Surface plasmon resonance, in vitro synaptogenesis assay with cortical neurons\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding affinity measured by SPR (a rigorous biophysical method), corroborated by functional synaptogenesis assay, replicated across labs\",\n      \"pmids\": [\"21356198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CBLN4 and Netrin-1 are identified as extracellular binding partners of DCC using protein microarray screens. CBLN4 binds to DCC at an overlapping site within membrane-proximal fibronectin domains FN4-6, with Netrin-1 competing with CBLN4 binding and exhibiting ~5-fold higher affinity. CBLN4 also binds to DCC homolog Neogenin-1 (NEO1) with lower affinity than DCC.\",\n      \"method\": \"Extracellular protein microarray screen (>1000 proteins), immunofluorescence, radio-ligand binding competition assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative radio-ligand binding with competition assay defining binding site, supported by independent microarray discovery and orthogonal fluorescence methods\",\n      \"pmids\": [\"24400119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of the C1q domain homotrimers of Cbln1 and Cbln4 were solved at 2.2 Å and 2.3 Å resolution, respectively. Structural comparison revealed that sequence and structural divergence in loop CD accounts for the difference in GluD2 binding between Cbln1 and Cbln4. Cbln4 was shown to form a stable complex with the LNS domain of Nrxn1β, and negative-stain EM reconstruction suggested Nrxn1β binds to the N-terminal region of Cbln4 through strand β10 of the S4 insert.\",\n      \"method\": \"X-ray crystallography, negative-stain electron microscopy, surface plasmon resonance (stable complex formation)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures at near-atomic resolution with EM structural reconstruction of the complex and functional binding validation\",\n      \"pmids\": [\"28877468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Glycosylation of Cbln4 at two N-linked sites attenuates receptor binding: the N-terminal glycosylation site masks neurexin binding, while the C1q domain glycosylation site masks GluD2 binding. Glycosylation mutants (asparagine-to-glutamine) of Cbln4 completely rescued ataxia in Cbln1-null mice in vivo, demonstrating that Cbln4 has intrinsic GluD2 binding that is masked by glycosylation.\",\n      \"method\": \"Site-directed mutagenesis of glycosylation sites, in vitro receptor binding assay, transgenic mouse rescue experiment\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with in vitro binding assay and in vivo rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29782851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cbln4 is selectively co-expressed with a specific neurexin splice isoform (lacking the SS4 insert) in parvalbumin-positive (PV+) interneurons of the mouse hippocampus. Conditional ablation of neurexin alternative splice insertions selectively in PV+ cells results in elevated hippocampal network activity and learning impairment, placing Cbln4 in a PV-interneuron-specific neurexin signaling pathway.\",\n      \"method\": \"Conditional knockout mouse, electrophysiology, behavioral testing, in situ hybridization, alternative splicing analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with conditional KO and multiple functional readouts, single lab\",\n      \"pmids\": [\"27960072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Constitutive Cbln4 knockout mice are viable and fertile, and single Cbln4 deletion does not produce the striatal synaptic changes seen in Cbln1-null mice. Combined Cbln1/2/4 triple KO aggravates salience-induced seizures observed in Cbln1/2 double KO, indicating Cbln4 contributes to brain function redundantly with other cerebellins. Cerebellins including Cbln4 are not required for initial synapse formation but contribute to long-term synapse maintenance.\",\n      \"method\": \"Constitutive single, double, and triple knockout mice; synapse density quantification; behavioral phenotyping (motor, seizure)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous genetic ablation study with multiple KO combinations and anatomical/behavioral readouts, single lab\",\n      \"pmids\": [\"29691328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cbln4 is a direct transcriptional target of SRY and SOX9 in the developing mouse testis. Anti-SRY chromatin immunoprecipitation pulled down a region 7.5 kb upstream of the Cbln4 transcriptional start site. Reducing Sox9 expression in XY mice decreased Cbln4 expression, overexpressing Sox9 in XX mice upregulated Cbln4, and ectopic SRY expression caused ectopic Cbln4 expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), transgenic mouse overexpression/knockdown, in situ expression analysis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP identifies direct genomic binding site, replicated by multiple transgenic gain- and loss-of-function models\",\n      \"pmids\": [\"19211811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cbln4 plays an essential role in the formation and maintenance of inhibitory GABAergic connections in cultured hippocampal neurons. Hes1 transcription factor controls Cbln4 expression downstream of NGF. Overexpression of Cbln4 or application of recombinant Cbln4 increased GABAergic varicosities and rescued neurons from Aβ-induced death; knockdown of Cbln4 reduced GABAergic connections.\",\n      \"method\": \"Cbln4 overexpression and knockdown in cultured hippocampal neurons, recombinant protein application, immunostaining for GABAergic markers (VGAT), Aβ toxicity rescue assay\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in cultured neurons with morphological synaptic readouts, single lab\",\n      \"pmids\": [\"25534236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cbln4, expressed presynaptically in entorhinal cortex neurons and bound to neurexins, forms transcellular complexes with postsynaptic neogenin-1 (NEO1) in dentate gyrus granule cells. Presynaptic deletion of Cbln4 or postsynaptic deletion of NEO1 (but not DCC) in dentate granule cells blocked long-term potentiation (LTP) at entorhinal cortex→dentate gyrus synapses without affecting basal synaptic transmission, establishing a Cbln4–neogenin-1 trans-synaptic signaling pathway required for LTP competence.\",\n      \"method\": \"Conditional knockout mice (presynaptic Cbln4 deletion; postsynaptic NEO1 and DCC deletions), electrophysiology (LTP induction and basal synaptic transmission)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic epistasis with cell-type-specific conditional KOs of both presynaptic and postsynaptic components, with specific electrophysiological readout distinguishing LTP from basal transmission\",\n      \"pmids\": [\"35544694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A GRID1 variant at a position predicted to interact with Cbln2/Cbln4 disrupts complex formation between GluD1 and Cbln2, identifying the GluD1 distal amino terminal domain as a site of interaction with Cbln4-related ligands.\",\n      \"method\": \"Site-directed mutagenesis of GRID1 variants, biochemical complex formation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single mutagenesis experiment with Cbln2; Cbln4 interaction inferred from predicted structural similarity, not directly tested for Cbln4\",\n      \"pmids\": [\"37944084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14-mediated m6A methylation improves the stability and expression of CBLN4 mRNA. In Aβ1-42-treated SK-N-SH cells, CBLN4 and METTL14 are both downregulated; overexpression of CBLN4 relieves apoptosis, inflammation, oxidative stress, and ER stress. METTL14 was shown to regulate CBLN4 mRNA stability via m6A modification using MeRIP and dual-luciferase reporter assays.\",\n      \"method\": \"MeRIP (methylated RNA immunoprecipitation), dual-luciferase reporter assay, overexpression in SK-N-SH cells, MTT, flow cytometry, ELISA, Western blot\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and dual-luciferase reporter directly demonstrate m6A-mediated mRNA stability regulation, with functional cellular readouts, single lab\",\n      \"pmids\": [\"39235700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Single-cell transcriptomic analysis across 17 developmental stages identifies NEOGENIN-1 as the principal postsynaptic receptor for CBLN4 during the perinatal period, mediating synapse formation between somatostatin-expressing interneurons and glutamatergic neurons in the mouse cortex.\",\n      \"method\": \"Single-cell transcriptomics across developmental stages, ligand-receptor inference\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational ligand-receptor inference from transcriptomic data; no direct binding or functional experiment reported in the abstract for this specific interaction\",\n      \"pmids\": [\"41565644\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBLN4 is a secreted N-linked glycoprotein member of the C1q/cerebellin family that forms homomeric and heteromeric complexes with other cerebellins; it binds selectively to DCC and neogenin-1 (not neurexins/GluD2 under normal glycosylation) and acts as a trans-synaptic organizer—presynaptically anchored via neurexins and interacting postsynaptically with neogenin-1 to confer LTP competence at entorhinal cortex→dentate gyrus synapses, promotes GABAergic synapse formation in hippocampal neurons, is transcriptionally regulated by SRY/SOX9 in the testis and by Hes1 in neurons, and its mRNA stability is controlled by METTL14-mediated m6A methylation; glycosylation at two N-linked sites attenuates its intrinsic GluD2 and neurexin binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CBLN4 is a secreted N-linked glycoprotein of the C1q/cerebellin family that functions as a trans-synaptic organizer, contributing redundantly with other cerebellins to synapse maintenance and plasticity rather than initial synapse formation [#0, #8]. It is secreted as a glycoprotein and assembles into both homomeric and heteromeric complexes with other cerebellins, and complex subunit composition tunes receptor selectivity—Cbln1/Cbln4 heteromers lose affinity for DCC while gaining affinity for neurexins [#0, #1]. Unlike Cbln1 and Cbln2, Cbln4 binds only weakly to neurexins and is poorly synaptogenic in standard neuronal cultures [#2, #3], a difference explained by glycosylation: N-linked glycans at an N-terminal site and within the C1q domain mask intrinsic neurexin and GluD2 binding, respectively, and removing these glycans unmasks GluD2 binding sufficient to rescue ataxia in Cbln1-null mice [#6]. Crystal structures of the Cbln4 C1q-domain homotrimer localize the GluD2-binding divergence to loop CD and define a stable Nrxn1\\u03b2 LNS-domain complex [#5]. CBLN4 binds selectively to the netrin receptor DCC and its homolog neogenin-1 (NEO1) at membrane-proximal fibronectin domains FN4-6, in a netrin-displaceable manner [#1, #4]. Physiologically, presynaptic CBLN4 anchored via neurexins in entorhinal cortex neurons engages postsynaptic NEO1 (not DCC) in dentate gyrus granule cells to confer long-term potentiation competence without affecting basal transmission [#11], and it promotes formation and maintenance of GABAergic connections in hippocampal neurons [#10]. Cbln4 expression is directly driven by SRY/SOX9 in the developing testis [#9] and by Hes1 downstream of NGF in neurons [#10], and its mRNA stability is enhanced by METTL14-mediated m6A methylation [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the basic biochemical nature of CBLN4 as a secreted glycoprotein capable of multimerizing with other cerebellins, raising the question of how heteromer composition shapes function.\",\n      \"evidence\": \"Mammalian heterologous expression with secretion assays, co-IP, and subcellular fractionation\",\n      \"pmids\": [\"17331201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and physiological prevalence of specific heteromers in vivo not defined\", \"No receptor binding tested at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified DCC as a selective CBLN4 receptor and showed that heteromer composition switches receptor preference between DCC and neurexins, linking subunit assembly to signaling output.\",\n      \"evidence\": \"Candidate receptor binding/pulldown with netrin displacement competition and Cbln4-null mice\",\n      \"pmids\": [\"22220752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on DCC not mapped\", \"Functional consequence of DCC engagement not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Distinguished CBLN4 from synaptogenic cerebellins by demonstrating it binds neurexins only weakly and lacks synaptogenic activity in vitro, indicating a divergent functional role.\",\n      \"evidence\": \"Surface plasmon resonance and in vitro synaptogenesis assays in cortical, hippocampal, and cerebellar neurons across two labs\",\n      \"pmids\": [\"21356198\", \"21410790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why CBLN4 is non-synaptogenic despite cerebellin homology unresolved at this stage\", \"In vivo synaptic role untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the molecular CBLN4-DCC interaction surface and extended receptor repertoire to neogenin-1, establishing competitive cross-talk with netrin-1.\",\n      \"evidence\": \"Extracellular protein microarray screen plus radio-ligand binding competition mapping to FN4-6 domains\",\n      \"pmids\": [\"24400119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular/synaptic readout of the CBLN4-DCC/NEO1 interaction not yet shown\", \"Affinity hierarchy among receptors not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided atomic-resolution structural basis for cerebellin functional divergence, localizing GluD2-binding specificity to loop CD and visualizing the Nrxn1\\u03b2 complex.\",\n      \"evidence\": \"X-ray crystallography of C1q homotrimers, negative-stain EM, and SPR\",\n      \"pmids\": [\"28877468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the receptor-bound (DCC/NEO1) complex not solved\", \"Role of glycosylation not addressed structurally\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved why CBLN4 appears non-synaptogenic by showing N-linked glycosylation masks intrinsic neurexin and GluD2 binding, with deglycosylated CBLN4 functionally substituting for Cbln1 in vivo.\",\n      \"evidence\": \"Glycosylation-site mutagenesis, in vitro binding, and transgenic rescue of Cbln1-null ataxia\",\n      \"pmids\": [\"29782851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether glycosylation is dynamically regulated in vivo unknown\", \"Cell-type-specific glycoforms not characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the in vivo significance of CBLN4 through genetic ablation, showing it acts redundantly with other cerebellins in synapse maintenance rather than initial formation.\",\n      \"evidence\": \"Single, double, and triple cerebellin knockout mice with synapse density and behavioral phenotyping\",\n      \"pmids\": [\"29691328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific synapses uniquely dependent on Cbln4 not identified here\", \"Molecular partner mediating maintenance not pinpointed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a defined circuit-level function by showing presynaptic CBLN4 signals to postsynaptic neogenin-1 to confer LTP competence at entorhinal cortex\\u2192dentate gyrus synapses.\",\n      \"evidence\": \"Cell-type-specific conditional KOs of presynaptic Cbln4 and postsynaptic NEO1 versus DCC with LTP and basal transmission electrophysiology\",\n      \"pmids\": [\"35544694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream NEO1 signaling underlying LTP not defined\", \"Generalizability to other circuits untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified CBLN4 as a direct SRY/SOX9 transcriptional target in the testis, revealing a developmental, non-neuronal regulatory context.\",\n      \"evidence\": \"Anti-SRY ChIP and transgenic gain/loss-of-function in mouse gonad\",\n      \"pmids\": [\"19211811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of CBLN4 in testis development unknown\", \"Downstream effectors not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed CBLN4 in an NGF/Hes1-controlled program promoting GABAergic connectivity and neuronal survival under amyloid stress.\",\n      \"evidence\": \"Overexpression, knockdown, and recombinant protein application in cultured hippocampal neurons with GABAergic marker staining and A\\u03b2 toxicity rescue\",\n      \"pmids\": [\"25534236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of GABAergic role lacking\", \"Receptor mediating GABAergic effect not specified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a post-transcriptional control layer, with METTL14-mediated m6A methylation stabilizing CBLN4 mRNA in a neuronal stress model.\",\n      \"evidence\": \"MeRIP and dual-luciferase reporter assays with CBLN4 overexpression in A\\u03b2-treated SK-N-SH cells\",\n      \"pmids\": [\"39235700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A sites not mapped at nucleotide resolution\", \"In vivo relevance to neural function untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated the GluD1 distal amino-terminal domain as an interaction site for Cbln4-related ligands via a disease-associated GRID1 variant.\",\n      \"evidence\": \"Site-directed mutagenesis and biochemical complex formation assay (tested directly with Cbln2)\",\n      \"pmids\": [\"37944084\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cbln4 interaction inferred from structural similarity, not directly tested\", \"Functional consequence of GluD1-Cbln4 binding unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Nominated neogenin-1 as the principal perinatal postsynaptic receptor mediating CBLN4-dependent somatostatin-interneuron-to-glutamatergic synapse formation in cortex.\",\n      \"evidence\": \"Single-cell transcriptomics across developmental stages with computational ligand-receptor inference\",\n      \"pmids\": [\"41565644\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational inference without direct binding or functional validation for this interaction\", \"Cortical interneuron synapse role not experimentally confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CBLN4 glycosylation state, heteromer composition, and receptor choice (DCC vs NEO1 vs GluD) are coordinated to specify distinct synaptic functions across brain regions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CBLN4 bound to DCC/NEO1\", \"Downstream intracellular signaling from NEO1 unknown\", \"Regulation of glycoform diversity in vivo undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 4, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [11, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DCC\", \"NEO1\", \"NRXN1\", \"GRID2\", \"CBLN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}