{"gene":"ADGRB3","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2011,"finding":"All four C1q-like proteins (C1ql1-C1ql4) bind to the extracellular thrombospondin-repeat domain of BAI3 with high affinity, mediated by the globular C1q domains of the C1ql proteins; addition of submicromolar C1ql proteins to cultured neurons decreased synapse density, and this was prevented by the thrombospondin-repeat fragment of BAI3.","method":"Biochemical binding assay (pulldown), neuronal culture synapse density assay with recombinant protein competition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding assay with domain-mapping, functional neuronal culture assay, multiple C1ql family members tested, replicated by multiple subsequent studies","pmids":["21262840"],"is_preprint":false},{"year":2014,"finding":"BAI3 interacts with ELMO1/2 at the cell surface and is required for myoblast fusion in vertebrates; loss of BAI3 or ELMO1/2 severely impairs myoblast fusion without affecting differentiation, and BAI3 mutants deficient in ELMO binding cannot rescue the fusion defect; BAI1 cannot functionally substitute for BAI3 in this process.","method":"Co-immunoprecipitation, loss-of-function (siRNA/dominant-negative), in vivo embryonic muscle expression of ELMO-binding-deficient BAI3 mutant","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-mutant rescue experiments in vitro and in vivo, replicated in subsequent studies","pmids":["24567399"],"is_preprint":false},{"year":2013,"finding":"BAI3 controls dendritic arborization growth and branching in neurons via activation of the RhoGTPase Rac1 and requires direct binding to ELMO1; knockdown of BAI3 or expression of ELMO-binding-deficient BAI3 in Purkinje cells in vivo impairs dendrite morphogenesis.","method":"Expression knockdown (shRNA/lentivirus), overexpression, transgenic mouse Purkinje cell-specific dominant-negative, Rac1 activation assay","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro knockdown and overexpression corroborated by in vivo transgenic and lentiviral experiments with defined cellular phenotype","pmids":["23628982"],"is_preprint":false},{"year":2015,"finding":"The C1QL1–BAI3 signaling pathway controls the stereotyped synaptic connectivity of excitatory afferents (parallel fibers and climbing fibers) on cerebellar Purkinje cells; restricted expression of C1QL1 in inferior olivary neurons determines proper climbing fiber synaptic territory.","method":"In vivo loss-of-function (knockout/knockdown), electrophysiology, immunohistochemistry in mouse cerebellum","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function with defined synaptic phenotype, multiple afferent types examined, replicated by later studies","pmids":["25660030"],"is_preprint":false},{"year":2018,"finding":"Stabilin-2 interacts with BAI3 and activates its GPCR activity, leading to recruitment of heterotrimeric G-proteins; activated G-proteins contribute to initial recruitment of ELMO proteins to the membrane, which are then stabilized on BAI3 through direct interaction, promoting myoblast fusion. C1q-like proteins (C1ql1-4) repress BAI3-mediated fusion by specifically interacting with BAI3. Mice lacking BAI3 display small muscle fibers and inefficient muscle regeneration after injury.","method":"Proteomic interactome screen, Co-IP, GPCR activity assay (BRET), BAI3 knockout mouse (cardiotoxin injury model), loss-of-function in myoblasts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — proteomic identification of Stabilin-2, GPCR activity assay, KO mouse phenotype, direct binding assays, multiple orthogonal methods in one study","pmids":["30367035"],"is_preprint":false},{"year":2018,"finding":"BAI3 mediates the inhibitory effects of C1ql3 on insulin secretion from pancreatic β-cells; C1ql3 inhibits primarily cAMP-stimulated insulin secretion, and siRNA-mediated Bai3 knockdown increases glucose-stimulated insulin secretion; the soluble C1ql3-binding fragment of BAI3 blocks C1ql3's inhibitory effects on cAMP-stimulated insulin secretion.","method":"siRNA knockdown in INS1(832/13) cells, recombinant protein competition assay, insulin secretion assay, cAMP measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with defined secretion phenotype plus competition with soluble receptor fragment, single lab, two complementary methods","pmids":["30228187"],"is_preprint":false},{"year":2021,"finding":"C1QL3 mediates formation of a novel trans-synaptic adhesion complex involving ADGRB3/BAI3 and neuronal pentraxins NPTX1 and NPTXR; C1QL3 bridges ADGRB3 and the pentraxins in a cell-cell adhesion complex identified by in vivo interactome study.","method":"In vivo interactome (co-IP/MS), cell-cell adhesion assay, single-cell RNA-seq co-expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Co-IP/MS identification plus cell adhesion functional assay, single lab","pmids":["33337553"],"is_preprint":false},{"year":2019,"finding":"BAI3 (as a putative C1QL4 receptor) is expressed in seminiferous tubules and Leydig cells of the testis; Bai3 knockdown in Leydig cells reduces StAR expression and alters ERK1/2 phosphorylation and cAMP levels, indicating a role in steroidogenesis; C1QL4-induced StAR expression was not completely suppressed in Bai3-deficient cells, suggesting an additional unidentified receptor.","method":"siRNA knockdown in TM3 Leydig cells, Western blot, cAMP measurement, StAR expression assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA KD with defined steroidogenic phenotype, single lab, partial mechanistic follow-up noting incomplete suppression indicating additional receptor","pmids":["30608882"],"is_preprint":false},{"year":2023,"finding":"C1ql1–Bai3 signaling in adult cerebellum regulates climbing fiber synaptogenesis in mature Purkinje cells; overexpression of C1ql1 or Bai3 caused CF transverse branches to elongate and synapse on distal PC dendrites; GluD2 knockout-induced CF reinnervation was absent in Bai3 knockout PCs, placing Bai3 downstream of GluD2; C1ql1 levels increased in GluD2 KO CF, suggesting endogenous C1ql1-Bai3 signaling regulates reinnervation; effects required neuronal activity in both PCs and CFs.","method":"Genetic epistasis (Bai3 KO × GluD2 KO double mutant), overexpression, electrophysiology, Ca2+-imaging, immunohistochemistry in mouse cerebellum","journal":"Molecular brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-KO epistasis, multiple orthogonal methods (electrophysiology, imaging, IHC), in vivo genetic evidence placing Bai3 downstream of GluD2 in CF synaptogenesis","pmids":["37488606"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of the C1ql3–BAI3 complex at 2.8 Å resolution reveals a hexameric configuration: a central C1ql3 homotrimer captures three BAI3 molecules that fit into the grooves between trimeric C1q domains via calcium ion (Ca2+)-mediated interactions; mutant analysis confirmed essential contact residues.","method":"Single-particle cryo-EM (2.8 Å), site-directed mutagenesis, cell surface staining","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with mutagenesis validation of contact residues, single lab but high-resolution structural method","pmids":["40316654"],"is_preprint":false},{"year":2025,"finding":"The trimeric gC1q domain of C1ql1 undergoes a calcium-modulated domain-swapping event to form a hexamer; cryo-EM structure reveals calcium ions stabilize the C1ql1 gC1q hexamer in complex with the extended CUB domain of BAI3; full-length C1ql1 further assembles into linear clusters to scaffold and accumulate BAI3 receptors on the plasma membrane; in vivo data support a role for gC1q-mediated dynamic assembly in receptor accumulation and synapse maintenance.","method":"Cryo-EM, biochemical reconstitution, computational analysis, cellular and in vivo studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with biochemical reconstitution and in vivo functional validation, single lab but multiple orthogonal methods","pmids":["41372137"],"is_preprint":false},{"year":2023,"finding":"Whole-body BAI3 knockout mice (CRISPR/Cas9, 7-bp deletion in exon 10) lack full-length ADGRB3 protein and display reduced brain and body weights and deficits in social interaction; locomotor function, olfaction, anxiety, and prepulse inhibition were not significantly different from wild-type.","method":"CRISPR/Cas9 knockout mouse, Western blot, behavioral testing","journal":"Basic & clinical pharmacology & toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with confirmed protein loss, defined behavioral phenotype, single lab","pmids":["37337931"],"is_preprint":false},{"year":2023,"finding":"Whole-body BAI3 knockout mice show increased energy expenditure and reduced body weight, with increased mRNA of thermogenic genes (Ucp1, Pgc1α, Prdm16, Elov3) in brown adipose tissue; energy expenditure differences were abolished at thermoneutrality (30°C), indicating a role for BAI3 in adaptive thermogenesis.","method":"CRISPR/Cas9 whole-body KO mouse, CLAMS metabolic monitoring, quantitative MRI, gene expression analysis","journal":"Metabolites","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined metabolic phenotype and thermoneutrality reversal control, single lab","pmids":["37367869"],"is_preprint":false},{"year":1997,"finding":"BAI3 (then named BAI3) is specifically expressed in brain and maps to chromosomal locus 6q12; unlike BAI1, BAI3 expression is not transcriptionally regulated by p53; BAI3 expression is absent or significantly reduced in multiple glioblastoma cell lines.","method":"Northern blot, chromosomal mapping, cell line expression analysis","journal":"Cytogenetics and cell genetics","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — expression and mapping data, no mechanistic assay beyond transcriptional regulation comparison","pmids":["9533023"],"is_preprint":false}],"current_model":"ADGRB3/BAI3 is an adhesion-GPCR expressed predominantly in the brain and muscle that functions as a high-affinity receptor for secreted C1q-like proteins (C1ql1–4) binding via its extracellular thrombospondin-repeat/CUB domains, with cryo-EM structures revealing calcium-mediated hexameric C1ql–BAI3 complexes; at synapses, the C1ql–BAI3 axis organizes excitatory synapse formation, maintenance, and climbing fiber connectivity in the cerebellum; in muscle, BAI3 activity is spatiotemporally regulated by C1qls (repressive) and Stabilin-2 (activating), and its GPCR activity drives ELMO/DOCK1-dependent Rac1 activation and myoblast fusion; in neurons BAI3 also controls dendritic arborization via ELMO1–Rac1 signaling; additionally BAI3 mediates C1ql3-dependent inhibition of cAMP-stimulated insulin secretion in pancreatic β-cells and regulates adaptive thermogenesis and brown adipose tissue activity."},"narrative":{"mechanistic_narrative":"ADGRB3 (BAI3) is an adhesion-GPCR that functions as a high-affinity receptor for the secreted C1q-like proteins (C1ql1–4), coupling extracellular C1ql recognition to intracellular Rac1-dependent cytoskeletal and adhesive remodeling across neuronal, muscle, and metabolic tissues [PMID:21262840, PMID:23628982, PMID:30367035]. The four C1ql proteins bind the extracellular thrombospondin-repeat domain of BAI3 through their globular C1q domains, and cryo-EM reveals that this interaction is calcium-mediated: a central C1ql homotrimer captures three BAI3 molecules into the grooves of the trimeric C1q domains, with C1ql further undergoing calcium-modulated domain-swapping to form hexamers and linear clusters that scaffold and accumulate BAI3 receptors at the plasma membrane [PMID:40316654, PMID:41372137]. Downstream, BAI3 binds ELMO1/2 directly at the cell surface and activates Rac1, a module that drives dendritic arborization in Purkinje cells and is required for vertebrate myoblast fusion, with ELMO-binding-deficient BAI3 mutants failing to rescue either phenotype [PMID:24567399, PMID:23628982]. In muscle, BAI3 GPCR activity is bidirectionally controlled — repressed by C1ql proteins and activated by Stabilin-2, which triggers heterotrimeric G-protein and ELMO recruitment to promote fusion and efficient muscle regeneration [PMID:30367035]. At cerebellar synapses, C1ql1–BAI3 signaling organizes the stereotyped connectivity of climbing and parallel fiber excitatory afferents onto Purkinje cells and regulates activity-dependent climbing fiber synaptogenesis downstream of GluD2 [PMID:25660030, PMID:37488606]. Beyond the nervous system and muscle, BAI3 mediates C1ql3-dependent inhibition of cAMP-stimulated insulin secretion in pancreatic β-cells and regulates adaptive thermogenesis, with knockout mice showing increased energy expenditure and thermogenic gene induction in brown adipose tissue [PMID:30228187, PMID:37367869].","teleology":[{"year":1997,"claim":"Established BAI3 as a brain-specific transcript distinct from its paralog BAI1, setting the stage for tissue-targeted functional study.","evidence":"Northern blot, chromosomal mapping to 6q12, and cell-line expression analysis","pmids":["9533023"],"confidence":"Low","gaps":["No mechanistic assay beyond transcriptional regulation comparison","No ligand or signaling function identified","Reduced expression in glioblastoma lines left mechanistically unexplained"]},{"year":2011,"claim":"Identified the C1q-like proteins as BAI3 ligands and mapped the binding interface, answering what BAI3 recognizes and linking it to synapse regulation.","evidence":"Pulldown binding assay with domain mapping and neuronal culture synapse-density competition assay","pmids":["21262840"],"confidence":"High","gaps":["Did not resolve downstream signaling from the receptor","Synapse effect direction (decrease) not yet reconciled with later synaptogenic roles"]},{"year":2013,"claim":"Connected BAI3 to an intracellular effector pathway, showing it drives dendrite morphogenesis through direct ELMO1 binding and Rac1 activation.","evidence":"shRNA knockdown, overexpression, transgenic Purkinje-cell dominant-negative, and Rac1 activation assay","pmids":["23628982"],"confidence":"High","gaps":["Did not link ELMO/Rac1 output to a defined ligand input","DOCK1 involvement not directly demonstrated here"]},{"year":2014,"claim":"Extended the BAI3–ELMO module beyond neurons, demonstrating it is required for vertebrate myoblast fusion and that the ELMO interaction is functionally essential.","evidence":"Reciprocal Co-IP, loss-of-function, and in vivo rescue with ELMO-binding-deficient mutant","pmids":["24567399"],"confidence":"High","gaps":["Upstream activator of BAI3 in muscle not yet identified","GPCR signaling step between receptor and ELMO not resolved"]},{"year":2015,"claim":"Placed the C1QL1–BAI3 axis in vivo as an organizer of stereotyped cerebellar afferent connectivity.","evidence":"In vivo knockout/knockdown, electrophysiology, and immunohistochemistry in mouse cerebellum","pmids":["25660030"],"confidence":"High","gaps":["Molecular mechanism of synaptic territory specification not fully resolved","Did not establish the structural basis of C1QL1–BAI3 binding"]},{"year":2018,"claim":"Resolved the bidirectional regulation of BAI3 GPCR activity in muscle, identifying Stabilin-2 as an activator and C1ql proteins as repressors upstream of G-protein/ELMO recruitment.","evidence":"Proteomic interactome, Co-IP, BRET GPCR activity assay, and BAI3 knockout cardiotoxin injury model","pmids":["30367035"],"confidence":"High","gaps":["Identity of coupled G-protein subtype not fully defined","How C1ql binding mechanically represses G-protein coupling unresolved"]},{"year":2018,"claim":"Demonstrated a non-neuronal endocrine role, showing BAI3 transduces C1ql3 inhibition of cAMP-stimulated insulin secretion in β-cells.","evidence":"siRNA knockdown in INS1 cells, soluble receptor-fragment competition, and insulin/cAMP secretion assays","pmids":["30228187"],"confidence":"Medium","gaps":["Single lab, two complementary methods","Signaling link between BAI3 and cAMP machinery not mapped","No in vivo confirmation in β-cells"]},{"year":2019,"claim":"Implicated BAI3 in testicular steroidogenesis as a C1QL4 receptor regulating StAR expression, while revealing it is not the sole receptor.","evidence":"siRNA knockdown in TM3 Leydig cells, Western blot, cAMP measurement, StAR expression assay","pmids":["30608882"],"confidence":"Medium","gaps":["Incomplete suppression indicates an additional unidentified C1QL4 receptor","Single lab","ERK1/2 and cAMP changes not mechanistically connected to receptor activation"]},{"year":2021,"claim":"Expanded the synaptic adhesion model by showing C1QL3 bridges ADGRB3 to neuronal pentraxins NPTX1/NPTXR in a trans-synaptic complex.","evidence":"In vivo Co-IP/MS interactome, cell-cell adhesion assay, and single-cell RNA-seq co-expression","pmids":["33337553"],"confidence":"Medium","gaps":["Single lab","Functional consequence of the BAI3–pentraxin complex at synapses not established","Stoichiometry of the multi-protein complex undefined"]},{"year":2023,"claim":"Positioned Bai3 within the molecular logic of activity-dependent cerebellar synaptogenesis, downstream of GluD2 in climbing fiber synapse regulation.","evidence":"Bai3 KO × GluD2 KO epistasis, overexpression, electrophysiology, Ca2+ imaging, and IHC","pmids":["37488606"],"confidence":"High","gaps":["Mechanistic link between GluD2 and C1ql1–Bai3 not defined","How neuronal activity gates the pathway unresolved"]},{"year":2023,"claim":"Defined organism-level consequences of BAI3 loss, revealing social-interaction deficits and a role in adaptive thermogenesis.","evidence":"CRISPR/Cas9 whole-body knockout mice with behavioral testing, CLAMS metabolic monitoring, MRI, and BAT gene expression","pmids":["37337931","37367869"],"confidence":"Medium","gaps":["Single lab for each phenotype","Cell-type and ligand responsible for thermogenic and behavioral phenotypes not pinpointed","Direct link to the C1ql–BAI3 axis not established for these phenotypes"]},{"year":2025,"claim":"Provided the structural mechanism of C1ql–BAI3 recognition, showing calcium-mediated hexameric assembly and domain-swapping that clusters receptors for synapse maintenance.","evidence":"Single-particle cryo-EM (2.8 Å), site-directed mutagenesis, biochemical reconstitution, and in vivo studies","pmids":["40316654","41372137"],"confidence":"High","gaps":["How ligand clustering is transduced to GPCR/G-protein activation not resolved","Structural basis of activating vs repressive signaling not addressed"]},{"year":null,"claim":"How extracellular C1ql binding and clustering is mechanically coupled to BAI3 GPCR activation, G-protein subtype selection, and the switch between repressive (C1ql) and activating (Stabilin-2) inputs remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of an activated, G-protein-coupled BAI3 state","G-protein subtype coupling not defined","Mechanism reconciling synapse-reducing and synapse-organizing effects of C1ql unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,9,10]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":["C1ql3–BAI3 hexameric complex","C1QL3–ADGRB3–NPTX1/NPTXR trans-synaptic adhesion complex"],"partners":["C1QL1","C1QL3","ELMO1","ELMO2","STAB2","NPTX1","NPTXR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60242","full_name":"Adhesion G protein-coupled receptor B3","aliases":["Brain-specific angiogenesis inhibitor 3"],"length_aa":1522,"mass_kda":171.5,"function":"Receptor that plays a role in the regulation of synaptogenesis and dendritic spine formation at least partly via interaction with ELMO1 and RAC1 activity (By similarity). Promotes myoblast fusion through ELMO/DOCK1 (PubMed:24567399)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O60242/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRB3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADGRB3","total_profiled":1310},"omim":[{"mim_id":"616945","title":"CLAVESIN 2; CLVS2","url":"https://www.omim.org/entry/616945"},{"mim_id":"602684","title":"ADHESION G PROTEIN-COUPLED RECEPTOR B3; ADGRB3","url":"https://www.omim.org/entry/602684"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":28.2},{"tissue":"pituitary gland","ntpm":21.3}],"url":"https://www.proteinatlas.org/search/ADGRB3"},"hgnc":{"alias_symbol":["KIAA0550"],"prev_symbol":["BAI3"]},"alphafold":{"accession":"O60242","domains":[{"cath_id":"-","chopping":"41-137_152-198","consensus_level":"high","plddt":55.1384,"start":41,"end":198},{"cath_id":"4.10.1240.10","chopping":"516-562","consensus_level":"medium","plddt":92.3719,"start":516,"end":562},{"cath_id":"1.25.40.610","chopping":"565-669","consensus_level":"medium","plddt":91.703,"start":565,"end":669},{"cath_id":"2.60.220.50","chopping":"693-867","consensus_level":"medium","plddt":86.7769,"start":693,"end":867},{"cath_id":"1.20.1070.10","chopping":"881-1049_1090-1161","consensus_level":"high","plddt":79.4274,"start":881,"end":1161}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60242","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60242-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60242-F1-predicted_aligned_error_v6.png","plddt_mean":63.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADGRB3","jax_strain_url":"https://www.jax.org/strain/search?query=ADGRB3"},"sequence":{"accession":"O60242","fasta_url":"https://rest.uniprot.org/uniprotkb/O60242.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60242/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60242"}},"corpus_meta":[{"pmid":"21262840","id":"PMC_21262840","title":"The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21262840","citation_count":151,"is_preprint":false},{"pmid":"25660030","id":"PMC_25660030","title":"The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25660030","citation_count":112,"is_preprint":false},{"pmid":"24567399","id":"PMC_24567399","title":"G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24567399","citation_count":98,"is_preprint":false},{"pmid":"9533023","id":"PMC_9533023","title":"Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1).","date":"1997","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9533023","citation_count":93,"is_preprint":false},{"pmid":"23628982","id":"PMC_23628982","title":"The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons.","date":"2013","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23628982","citation_count":75,"is_preprint":false},{"pmid":"15225653","id":"PMC_15225653","title":"Expression of brain-specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia-induced brain angiogenesis and malignant glioma.","date":"2004","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15225653","citation_count":61,"is_preprint":false},{"pmid":"30367035","id":"PMC_30367035","title":"Spatiotemporal regulation of the GPCR activity of BAI3 by 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/40316654","citation_count":7,"is_preprint":false},{"pmid":"28537194","id":"PMC_28537194","title":"An investigation into the potential role of brain angiogenesis inhibitor protein 3 (BAI3) in the tumorigenesis of small-cell carcinoma: a review of the surrounding literature.","date":"2017","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/28537194","citation_count":7,"is_preprint":false},{"pmid":"41372137","id":"PMC_41372137","title":"Structural basis of calcium-dependent C1ql1/BAI3 assemblies in synaptic connectivity.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41372137","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.02.636169","title":"Regulation of hippocampal excitatory synapse development by the adhesion G-protein coupled receptor Brain-specific angiogenesis inhibitor 2 (BAI2/ADGRB2)","date":"2025-02-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.02.636169","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.17.25333857","title":"The relationship between schizophrenia polygenic scores, blood-based proteins and psychosis diagnosis in the UK Biobank","date":"2025-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.17.25333857","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.10.607452","title":"Genomic Study of Taste Perception Genes in African Americans Reveals SNPs Linked to Alzheimer’s Disease","date":"2024-08-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.10.607452","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15743,"output_tokens":3748,"usd":0.051724,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11529,"output_tokens":4159,"usd":0.08081,"stage2_stop_reason":"end_turn"},"total_usd":0.132534,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"All four C1q-like proteins (C1ql1-C1ql4) bind to the extracellular thrombospondin-repeat domain of BAI3 with high affinity, mediated by the globular C1q domains of the C1ql proteins; addition of submicromolar C1ql proteins to cultured neurons decreased synapse density, and this was prevented by the thrombospondin-repeat fragment of BAI3.\",\n      \"method\": \"Biochemical binding assay (pulldown), neuronal culture synapse density assay with recombinant protein competition\",\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 — in vitro binding assay with domain-mapping, functional neuronal culture assay, multiple C1ql family members tested, replicated by multiple subsequent studies\",\n      \"pmids\": [\"21262840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BAI3 interacts with ELMO1/2 at the cell surface and is required for myoblast fusion in vertebrates; loss of BAI3 or ELMO1/2 severely impairs myoblast fusion without affecting differentiation, and BAI3 mutants deficient in ELMO binding cannot rescue the fusion defect; BAI1 cannot functionally substitute for BAI3 in this process.\",\n      \"method\": \"Co-immunoprecipitation, loss-of-function (siRNA/dominant-negative), in vivo embryonic muscle expression of ELMO-binding-deficient BAI3 mutant\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-mutant rescue experiments in vitro and in vivo, replicated in subsequent studies\",\n      \"pmids\": [\"24567399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAI3 controls dendritic arborization growth and branching in neurons via activation of the RhoGTPase Rac1 and requires direct binding to ELMO1; knockdown of BAI3 or expression of ELMO-binding-deficient BAI3 in Purkinje cells in vivo impairs dendrite morphogenesis.\",\n      \"method\": \"Expression knockdown (shRNA/lentivirus), overexpression, transgenic mouse Purkinje cell-specific dominant-negative, Rac1 activation assay\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro knockdown and overexpression corroborated by in vivo transgenic and lentiviral experiments with defined cellular phenotype\",\n      \"pmids\": [\"23628982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The C1QL1–BAI3 signaling pathway controls the stereotyped synaptic connectivity of excitatory afferents (parallel fibers and climbing fibers) on cerebellar Purkinje cells; restricted expression of C1QL1 in inferior olivary neurons determines proper climbing fiber synaptic territory.\",\n      \"method\": \"In vivo loss-of-function (knockout/knockdown), electrophysiology, immunohistochemistry in mouse cerebellum\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function with defined synaptic phenotype, multiple afferent types examined, replicated by later studies\",\n      \"pmids\": [\"25660030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Stabilin-2 interacts with BAI3 and activates its GPCR activity, leading to recruitment of heterotrimeric G-proteins; activated G-proteins contribute to initial recruitment of ELMO proteins to the membrane, which are then stabilized on BAI3 through direct interaction, promoting myoblast fusion. C1q-like proteins (C1ql1-4) repress BAI3-mediated fusion by specifically interacting with BAI3. Mice lacking BAI3 display small muscle fibers and inefficient muscle regeneration after injury.\",\n      \"method\": \"Proteomic interactome screen, Co-IP, GPCR activity assay (BRET), BAI3 knockout mouse (cardiotoxin injury model), loss-of-function in myoblasts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — proteomic identification of Stabilin-2, GPCR activity assay, KO mouse phenotype, direct binding assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30367035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAI3 mediates the inhibitory effects of C1ql3 on insulin secretion from pancreatic β-cells; C1ql3 inhibits primarily cAMP-stimulated insulin secretion, and siRNA-mediated Bai3 knockdown increases glucose-stimulated insulin secretion; the soluble C1ql3-binding fragment of BAI3 blocks C1ql3's inhibitory effects on cAMP-stimulated insulin secretion.\",\n      \"method\": \"siRNA knockdown in INS1(832/13) cells, recombinant protein competition assay, insulin secretion assay, cAMP measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with defined secretion phenotype plus competition with soluble receptor fragment, single lab, two complementary methods\",\n      \"pmids\": [\"30228187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1QL3 mediates formation of a novel trans-synaptic adhesion complex involving ADGRB3/BAI3 and neuronal pentraxins NPTX1 and NPTXR; C1QL3 bridges ADGRB3 and the pentraxins in a cell-cell adhesion complex identified by in vivo interactome study.\",\n      \"method\": \"In vivo interactome (co-IP/MS), cell-cell adhesion assay, single-cell RNA-seq co-expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Co-IP/MS identification plus cell adhesion functional assay, single lab\",\n      \"pmids\": [\"33337553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BAI3 (as a putative C1QL4 receptor) is expressed in seminiferous tubules and Leydig cells of the testis; Bai3 knockdown in Leydig cells reduces StAR expression and alters ERK1/2 phosphorylation and cAMP levels, indicating a role in steroidogenesis; C1QL4-induced StAR expression was not completely suppressed in Bai3-deficient cells, suggesting an additional unidentified receptor.\",\n      \"method\": \"siRNA knockdown in TM3 Leydig cells, Western blot, cAMP measurement, StAR expression assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA KD with defined steroidogenic phenotype, single lab, partial mechanistic follow-up noting incomplete suppression indicating additional receptor\",\n      \"pmids\": [\"30608882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"C1ql1–Bai3 signaling in adult cerebellum regulates climbing fiber synaptogenesis in mature Purkinje cells; overexpression of C1ql1 or Bai3 caused CF transverse branches to elongate and synapse on distal PC dendrites; GluD2 knockout-induced CF reinnervation was absent in Bai3 knockout PCs, placing Bai3 downstream of GluD2; C1ql1 levels increased in GluD2 KO CF, suggesting endogenous C1ql1-Bai3 signaling regulates reinnervation; effects required neuronal activity in both PCs and CFs.\",\n      \"method\": \"Genetic epistasis (Bai3 KO × GluD2 KO double mutant), overexpression, electrophysiology, Ca2+-imaging, immunohistochemistry in mouse cerebellum\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-KO epistasis, multiple orthogonal methods (electrophysiology, imaging, IHC), in vivo genetic evidence placing Bai3 downstream of GluD2 in CF synaptogenesis\",\n      \"pmids\": [\"37488606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of the C1ql3–BAI3 complex at 2.8 Å resolution reveals a hexameric configuration: a central C1ql3 homotrimer captures three BAI3 molecules that fit into the grooves between trimeric C1q domains via calcium ion (Ca2+)-mediated interactions; mutant analysis confirmed essential contact residues.\",\n      \"method\": \"Single-particle cryo-EM (2.8 Å), site-directed mutagenesis, cell surface staining\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with mutagenesis validation of contact residues, single lab but high-resolution structural method\",\n      \"pmids\": [\"40316654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The trimeric gC1q domain of C1ql1 undergoes a calcium-modulated domain-swapping event to form a hexamer; cryo-EM structure reveals calcium ions stabilize the C1ql1 gC1q hexamer in complex with the extended CUB domain of BAI3; full-length C1ql1 further assembles into linear clusters to scaffold and accumulate BAI3 receptors on the plasma membrane; in vivo data support a role for gC1q-mediated dynamic assembly in receptor accumulation and synapse maintenance.\",\n      \"method\": \"Cryo-EM, biochemical reconstitution, computational analysis, cellular and in vivo studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with biochemical reconstitution and in vivo functional validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41372137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Whole-body BAI3 knockout mice (CRISPR/Cas9, 7-bp deletion in exon 10) lack full-length ADGRB3 protein and display reduced brain and body weights and deficits in social interaction; locomotor function, olfaction, anxiety, and prepulse inhibition were not significantly different from wild-type.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse, Western blot, behavioral testing\",\n      \"journal\": \"Basic & clinical pharmacology & toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with confirmed protein loss, defined behavioral phenotype, single lab\",\n      \"pmids\": [\"37337931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Whole-body BAI3 knockout mice show increased energy expenditure and reduced body weight, with increased mRNA of thermogenic genes (Ucp1, Pgc1α, Prdm16, Elov3) in brown adipose tissue; energy expenditure differences were abolished at thermoneutrality (30°C), indicating a role for BAI3 in adaptive thermogenesis.\",\n      \"method\": \"CRISPR/Cas9 whole-body KO mouse, CLAMS metabolic monitoring, quantitative MRI, gene expression analysis\",\n      \"journal\": \"Metabolites\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined metabolic phenotype and thermoneutrality reversal control, single lab\",\n      \"pmids\": [\"37367869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"BAI3 (then named BAI3) is specifically expressed in brain and maps to chromosomal locus 6q12; unlike BAI1, BAI3 expression is not transcriptionally regulated by p53; BAI3 expression is absent or significantly reduced in multiple glioblastoma cell lines.\",\n      \"method\": \"Northern blot, chromosomal mapping, cell line expression analysis\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — expression and mapping data, no mechanistic assay beyond transcriptional regulation comparison\",\n      \"pmids\": [\"9533023\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADGRB3/BAI3 is an adhesion-GPCR expressed predominantly in the brain and muscle that functions as a high-affinity receptor for secreted C1q-like proteins (C1ql1–4) binding via its extracellular thrombospondin-repeat/CUB domains, with cryo-EM structures revealing calcium-mediated hexameric C1ql–BAI3 complexes; at synapses, the C1ql–BAI3 axis organizes excitatory synapse formation, maintenance, and climbing fiber connectivity in the cerebellum; in muscle, BAI3 activity is spatiotemporally regulated by C1qls (repressive) and Stabilin-2 (activating), and its GPCR activity drives ELMO/DOCK1-dependent Rac1 activation and myoblast fusion; in neurons BAI3 also controls dendritic arborization via ELMO1–Rac1 signaling; additionally BAI3 mediates C1ql3-dependent inhibition of cAMP-stimulated insulin secretion in pancreatic β-cells and regulates adaptive thermogenesis and brown adipose tissue activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADGRB3 (BAI3) is an adhesion-GPCR that functions as a high-affinity receptor for the secreted C1q-like proteins (C1ql1–4), coupling extracellular C1ql recognition to intracellular Rac1-dependent cytoskeletal and adhesive remodeling across neuronal, muscle, and metabolic tissues [#0, #2, #4]. The four C1ql proteins bind the extracellular thrombospondin-repeat domain of BAI3 through their globular C1q domains, and cryo-EM reveals that this interaction is calcium-mediated: a central C1ql homotrimer captures three BAI3 molecules into the grooves of the trimeric C1q domains, with C1ql further undergoing calcium-modulated domain-swapping to form hexamers and linear clusters that scaffold and accumulate BAI3 receptors at the plasma membrane [#9, #10]. Downstream, BAI3 binds ELMO1/2 directly at the cell surface and activates Rac1, a module that drives dendritic arborization in Purkinje cells and is required for vertebrate myoblast fusion, with ELMO-binding-deficient BAI3 mutants failing to rescue either phenotype [#1, #2]. In muscle, BAI3 GPCR activity is bidirectionally controlled — repressed by C1ql proteins and activated by Stabilin-2, which triggers heterotrimeric G-protein and ELMO recruitment to promote fusion and efficient muscle regeneration [#4]. At cerebellar synapses, C1ql1–BAI3 signaling organizes the stereotyped connectivity of climbing and parallel fiber excitatory afferents onto Purkinje cells and regulates activity-dependent climbing fiber synaptogenesis downstream of GluD2 [#3, #8]. Beyond the nervous system and muscle, BAI3 mediates C1ql3-dependent inhibition of cAMP-stimulated insulin secretion in pancreatic β-cells and regulates adaptive thermogenesis, with knockout mice showing increased energy expenditure and thermogenic gene induction in brown adipose tissue [#5, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established BAI3 as a brain-specific transcript distinct from its paralog BAI1, setting the stage for tissue-targeted functional study.\",\n      \"evidence\": \"Northern blot, chromosomal mapping to 6q12, and cell-line expression analysis\",\n      \"pmids\": [\"9533023\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic assay beyond transcriptional regulation comparison\", \"No ligand or signaling function identified\", \"Reduced expression in glioblastoma lines left mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the C1q-like proteins as BAI3 ligands and mapped the binding interface, answering what BAI3 recognizes and linking it to synapse regulation.\",\n      \"evidence\": \"Pulldown binding assay with domain mapping and neuronal culture synapse-density competition assay\",\n      \"pmids\": [\"21262840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve downstream signaling from the receptor\", \"Synapse effect direction (decrease) not yet reconciled with later synaptogenic roles\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected BAI3 to an intracellular effector pathway, showing it drives dendrite morphogenesis through direct ELMO1 binding and Rac1 activation.\",\n      \"evidence\": \"shRNA knockdown, overexpression, transgenic Purkinje-cell dominant-negative, and Rac1 activation assay\",\n      \"pmids\": [\"23628982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link ELMO/Rac1 output to a defined ligand input\", \"DOCK1 involvement not directly demonstrated here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the BAI3–ELMO module beyond neurons, demonstrating it is required for vertebrate myoblast fusion and that the ELMO interaction is functionally essential.\",\n      \"evidence\": \"Reciprocal Co-IP, loss-of-function, and in vivo rescue with ELMO-binding-deficient mutant\",\n      \"pmids\": [\"24567399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activator of BAI3 in muscle not yet identified\", \"GPCR signaling step between receptor and ELMO not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed the C1QL1–BAI3 axis in vivo as an organizer of stereotyped cerebellar afferent connectivity.\",\n      \"evidence\": \"In vivo knockout/knockdown, electrophysiology, and immunohistochemistry in mouse cerebellum\",\n      \"pmids\": [\"25660030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of synaptic territory specification not fully resolved\", \"Did not establish the structural basis of C1QL1–BAI3 binding\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the bidirectional regulation of BAI3 GPCR activity in muscle, identifying Stabilin-2 as an activator and C1ql proteins as repressors upstream of G-protein/ELMO recruitment.\",\n      \"evidence\": \"Proteomic interactome, Co-IP, BRET GPCR activity assay, and BAI3 knockout cardiotoxin injury model\",\n      \"pmids\": [\"30367035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of coupled G-protein subtype not fully defined\", \"How C1ql binding mechanically represses G-protein coupling unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a non-neuronal endocrine role, showing BAI3 transduces C1ql3 inhibition of cAMP-stimulated insulin secretion in β-cells.\",\n      \"evidence\": \"siRNA knockdown in INS1 cells, soluble receptor-fragment competition, and insulin/cAMP secretion assays\",\n      \"pmids\": [\"30228187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, two complementary methods\", \"Signaling link between BAI3 and cAMP machinery not mapped\", \"No in vivo confirmation in β-cells\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated BAI3 in testicular steroidogenesis as a C1QL4 receptor regulating StAR expression, while revealing it is not the sole receptor.\",\n      \"evidence\": \"siRNA knockdown in TM3 Leydig cells, Western blot, cAMP measurement, StAR expression assay\",\n      \"pmids\": [\"30608882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Incomplete suppression indicates an additional unidentified C1QL4 receptor\", \"Single lab\", \"ERK1/2 and cAMP changes not mechanistically connected to receptor activation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the synaptic adhesion model by showing C1QL3 bridges ADGRB3 to neuronal pentraxins NPTX1/NPTXR in a trans-synaptic complex.\",\n      \"evidence\": \"In vivo Co-IP/MS interactome, cell-cell adhesion assay, and single-cell RNA-seq co-expression\",\n      \"pmids\": [\"33337553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Functional consequence of the BAI3–pentraxin complex at synapses not established\", \"Stoichiometry of the multi-protein complex undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned Bai3 within the molecular logic of activity-dependent cerebellar synaptogenesis, downstream of GluD2 in climbing fiber synapse regulation.\",\n      \"evidence\": \"Bai3 KO × GluD2 KO epistasis, overexpression, electrophysiology, Ca2+ imaging, and IHC\",\n      \"pmids\": [\"37488606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between GluD2 and C1ql1–Bai3 not defined\", \"How neuronal activity gates the pathway unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined organism-level consequences of BAI3 loss, revealing social-interaction deficits and a role in adaptive thermogenesis.\",\n      \"evidence\": \"CRISPR/Cas9 whole-body knockout mice with behavioral testing, CLAMS metabolic monitoring, MRI, and BAT gene expression\",\n      \"pmids\": [\"37337931\", \"37367869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab for each phenotype\", \"Cell-type and ligand responsible for thermogenic and behavioral phenotypes not pinpointed\", \"Direct link to the C1ql–BAI3 axis not established for these phenotypes\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural mechanism of C1ql–BAI3 recognition, showing calcium-mediated hexameric assembly and domain-swapping that clusters receptors for synapse maintenance.\",\n      \"evidence\": \"Single-particle cryo-EM (2.8 Å), site-directed mutagenesis, biochemical reconstitution, and in vivo studies\",\n      \"pmids\": [\"40316654\", \"41372137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ligand clustering is transduced to GPCR/G-protein activation not resolved\", \"Structural basis of activating vs repressive signaling not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How extracellular C1ql binding and clustering is mechanically coupled to BAI3 GPCR activation, G-protein subtype selection, and the switch between repressive (C1ql) and activating (Stabilin-2) inputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of an activated, G-protein-coupled BAI3 state\", \"G-protein subtype coupling not defined\", \"Mechanism reconciling synapse-reducing and synapse-organizing effects of C1ql unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 9, 10]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"C1ql3–BAI3 hexameric complex\",\n      \"C1QL3–ADGRB3–NPTX1/NPTXR trans-synaptic adhesion complex\"\n    ],\n    \"partners\": [\n      \"C1QL1\",\n      \"C1QL3\",\n      \"ELMO1\",\n      \"ELMO2\",\n      \"STAB2\",\n      \"NPTX1\",\n      \"NPTXR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}