{"gene":"C1QL1","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2015,"finding":"C1QL1 (provided by climbing fibers as an anterograde signal) specifically binds to BAI3 (brain-specific angiogenesis inhibitor 3), a cell-adhesion G-protein-coupled receptor expressed on postsynaptic Purkinje cells, and this C1QL1-BAI3 signaling is required to determine and maintain a single-winner climbing fiber in the mouse cerebellum throughout development and adulthood.","method":"Genetic knockout, binding assays, electrophysiology, immunohistochemistry","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated, loss-of-function with defined cellular phenotype, independently replicated across two labs in the same year","pmids":["25611509"],"is_preprint":false},{"year":2015,"finding":"The C1QL1-BAI3 signaling pathway controls the stereotyped pattern of synaptic connectivity established by excitatory afferents (both climbing fibers and parallel fibers) on cerebellar Purkinje cells; restricted expression of C1QL1 in inferior olivary neurons ensures the proper synaptic territory for climbing fibers.","method":"Genetic knockout, overexpression, electrophysiology, immunohistochemistry","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined synaptic phenotype, replicates and extends findings from concurrent independent lab","pmids":["25660030"],"is_preprint":false},{"year":2016,"finding":"The globular domain of C1QL1/CTRP14 directly stimulates migration and capillary tube formation of HUVECs in a dose-dependent manner, activating phosphorylation of c-Raf, MEK1/2, ERK1/2, and p90RSK; MEK1/2 inhibition with U0126 blocks these effects. BAI3 immunoreactivity was detected in HUVECs, suggesting BAI3 mediates this proangiogenic effect.","method":"In vitro angiogenesis assay (HUVEC migration and tube formation), Western blot for phospho-ERK pathway components, pharmacological inhibition (U0126), chick yolk sac membrane assay","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional assays in one lab, BAI3 involvement inferred by immunoreactivity only (not proven by loss-of-function)","pmids":["27734226"],"is_preprint":false},{"year":2009,"finding":"C1QL1 pre-mRNA undergoes A-to-I RNA editing in vivo, causing non-synonymous amino acid substitutions, conserved across human, mouse, and zebrafish; the major editing site had previously been misannotated as a SNP.","method":"RNA sequencing, comparative genomics, RNA secondary structure analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing of edited transcripts in multiple species with structural analysis, single lab","pmids":["19275900"],"is_preprint":false},{"year":2023,"finding":"Overexpression of C1ql1 in climbing fibers or Bai3 in Purkinje cells causes transverse CF branches to elongate and form new synapses on distal dendrites of mature Purkinje cells; this reinnervation requires neuronal activity and is dependent on Bai3 in Purkinje cells. Additionally, C1ql1 levels in CFs are upregulated in GluD2 knockout mice, and the reinnervation phenotype of GluD2 KO is absent in Bai3 KO mice, placing C1ql1-Bai3 signaling downstream of GluD2-dependent synapse maintenance.","method":"Viral overexpression, conditional knockout, electrophysiology, Ca²⁺ imaging, immunohistochemistry, genetic epistasis (GluD2 KO × Bai3 KO double mutant)","journal":"Molecular brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double-mutant analysis, multiple orthogonal methods (electrophysiology + imaging + IHC), activity-dependence validation","pmids":["37488606"],"is_preprint":false},{"year":2021,"finding":"C1ql1 is expressed in outer hair cells of the cochlea in an adolescence-onset, tonotopic gradient pattern. Conditional knockout of C1ql1 in outer hair cells results in histological evidence of reduced outer hair cell afferent synapse maintenance, though auditory behavioral and physiological phenotypes were not compelling.","method":"Fluorescent reporter knockin mouse, conditional knockout, histology/immunohistochemistry, auditory brainstem response testing","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean conditional KO with histological readout but no significant functional phenotype, single lab","pmids":["33979385"],"is_preprint":false},{"year":2021,"finding":"C1ql1 global knockout mice exhibit progressive hearing loss with reduced auditory nerve fiber innervation of both inner and outer hair cells, and significant outer hair cell loss; however, spiral ganglion neurons are normal ultrastructurally, and IHC presynaptic machinery (synaptic vesicle release, presynaptic proteins) is not significantly affected by C1ql1 deletion.","method":"Global knockout mouse, auditory brainstem response, DPOAE, confocal microscopy, electron microscopy, voltage-clamp recording, immunocytochemistry","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, EM, confocal, ABR/DPOAE), clean KO with multiple specific phenotypic readouts","pmids":["34512267"],"is_preprint":false},{"year":2022,"finding":"C1QL1 deficiency in mice (via intraperitoneal and intrabursal injection of C1QL1 antiserum) impairs folliculogenesis, reduces granulosa cell autophagy, alleviates C1QL1-mediated inhibition of granulosa cell apoptosis, elevates circulating estradiol, reduces hypothalamic KISS1 and GnRH expression, and decreases serum FSH, leading to depletion of ovarian follicle reserve.","method":"Antibody-mediated blockade (IP + intrabursal injection), immunohistochemistry, ELISA for hormones, confocal microscopy for follicle staging","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple phenotypic readouts and pathway components examined but mechanism relies on antibody blockade (not genetic KO) and downstream signaling not directly linked","pmids":["35560215"],"is_preprint":false},{"year":2022,"finding":"CTRP14/C1QL1 deficiency in mice alters physical activity and food intake in a sex- and nutritional state-dependent manner (lower activity in fed males, increased activity in fasted/refed females, reduced food intake in refed males), but is largely dispensable for metabolic homeostasis, body composition, and insulin sensitivity.","method":"Constitutive knockout mouse, metabolic cage analysis (physical activity, food intake), body composition analysis, glucose tolerance test, insulin tolerance test, lipid profiling","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with multiple metabolic phenotypic readouts, single lab","pmids":["35403439"],"is_preprint":false},{"year":2024,"finding":"C1QL1 is expressed in oligodendrocyte progenitor cells (OPCs) and its deficiency (OPC-specific conditional KO) reduces OPC differentiation into oligodendrocytes and myelin production during development and after cuprizone-induced demyelination; conversely, in vivo overexpression of C1QL1 increases oligodendrocyte density and myelination during recovery. C1QL1 levels bidirectionally regulate OPC differentiation in primary culture.","method":"OPC-specific conditional knockout, in vivo viral overexpression, cuprizone demyelination model, primary OPC culture, immunohistochemistry","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional manipulation (KO + overexpression) with matching phenotypes in vivo and in vitro, clean cell-type-specific KO","pmids":["39257292"],"is_preprint":false},{"year":2025,"finding":"The trimeric globular C1q (gC1q) domain of C1ql1 undergoes calcium-modulated domain-swapping to form a hexamer; cryo-EM 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 via the gC1q hexamer, providing a scaffold to accumulate BAI3 receptors on the plasma membrane, supporting synapse maintenance.","method":"Cryo-EM structure determination, biochemical assembly assays, computational analysis, cellular and in vivo functional validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with biochemical and in vivo validation, multiple orthogonal methods in single study","pmids":["41372137"],"is_preprint":false},{"year":2025,"finding":"C1QL1 interacts with BAI3 in the cochlea (confirmed by colocalization and co-immunoprecipitation), and regulates auditory nerve fiber growth via the BAI3-ELMO1-DOCK180-RAC1 pathway; C1ql1 overexpression inhibits expression of the TIAM1-PARD3 pathway.","method":"Co-immunoprecipitation, colocalization imaging, overexpression/knockdown with pathway component analysis","journal":"Acta oto-laryngologica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP confirms interaction in cochlea, pathway components measured but not fully validated by epistasis, single lab","pmids":["40193629"],"is_preprint":false},{"year":2025,"finding":"In breast cancer, C1QL1 localizes to the endoplasmic reticulum and interacts with HSP90α and VCP (confirmed by co-immunoprecipitation and mass spectrometry), facilitating their ubiquitin-mediated degradation and thereby inducing ER stress/unfolded protein response (ERS/UPR) and caspase-dependent apoptosis. C1QL1 promoter methylation silences its expression in breast cancer.","method":"LC-MS/MS, co-immunoprecipitation, Western blot, overexpression/knockdown in vitro and in vivo (nude mice), flow cytometry (apoptosis/cell cycle), TUNEL, methylation-specific PCR","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and MS identify interactors, in vitro and in vivo functional readouts, single lab, mechanism partially inferred","pmids":["40583061"],"is_preprint":false},{"year":2026,"finding":"Glioblastoma-secreted C1QL1 binds to BAI3 on neighboring neurons and GBM cells, activating RAC1-mediated cytoskeleton rearrangement to prune normal synapses and promote tumor microtube (TM) outgrowth and malignant synapse formation; a non-GEF-targeting RAC1 inhibitor rescues C1QL1-mediated synaptic pruning and inhibits glioma recurrence.","method":"In vitro signaling assays, pharmacological inhibition (RAC1 inhibitor), in vivo glioma models, functional rescue experiments","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with pharmacological rescue, single lab, pathway placement via inhibitor but not full genetic epistasis","pmids":["41747254"],"is_preprint":false}],"current_model":"C1QL1 is a secreted trimeric C1q-family protein that, in its calcium-modulated hexameric form, binds the extracellular CUB domain of the adhesion-GPCR BAI3 to organize pre- and post-synaptic scaffolds; in the cerebellum it is transported anterogradely in climbing fiber axons to drive competitive synapse elimination and maintenance at the climbing fiber–Purkinje cell synapse, with downstream signaling proceeding through the BAI3-ELMO1-DOCK180-RAC1 cytoskeletal pathway, and it additionally promotes oligodendrocyte progenitor differentiation and myelination, regulates cochlear nerve fiber innervation, and in non-neural contexts can activate ERK1/2-dependent angiogenesis and modulate ER-stress-dependent apoptosis via interaction with HSP90α and VCP."},"narrative":{"mechanistic_narrative":"C1QL1 is a secreted C1q-family protein that functions as a synaptic organizer by binding the adhesion-GPCR BAI3 to control the establishment, maintenance, and elimination of excitatory synapses in the nervous system [PMID:25611509, PMID:25660030]. In the cerebellum, C1QL1 is supplied as an anterograde signal by climbing fibers and acts on postsynaptic Purkinje cells to determine and maintain a single-winner climbing fiber, with its restricted expression in inferior olivary neurons defining the climbing-fiber synaptic territory [PMID:25611509, PMID:25660030]; this C1QL1-BAI3 axis operates downstream of GluD2-dependent synapse maintenance and drives activity-dependent reinnervation of mature Purkinje cell dendrites [PMID:37488606]. Structurally, the trimeric globular gC1q domain undergoes calcium-modulated domain-swapping to assemble into a hexamer that engages the extended CUB domain of BAI3, and full-length C1QL1 forms linear clusters that accumulate BAI3 receptors at the plasma membrane to scaffold the synapse [PMID:41372137]. Beyond the cerebellum, C1QL1 interacts with BAI3 in the cochlea to regulate auditory nerve fiber growth and hair-cell afferent innervation via the BAI3-ELMO1-DOCK180-RAC1 cytoskeletal pathway, with global loss causing progressive hearing loss [PMID:34512267, PMID:40193629], and it bidirectionally regulates oligodendrocyte progenitor differentiation and myelination during development and remyelination [PMID:39257292]. In non-neural and disease contexts, the globular domain stimulates HUVEC migration and tube formation through ERK1/2 signaling [PMID:27734226], C1QL1 localizes to the endoplasmic reticulum where it binds HSP90α and VCP to promote their degradation and induce ER-stress-dependent apoptosis in breast cancer [PMID:40583061], and glioblastoma-secreted C1QL1 engages BAI3 to drive RAC1-mediated synaptic pruning and tumor microtube outgrowth [PMID:41747254].","teleology":[{"year":2015,"claim":"Established C1QL1's core function by identifying its receptor BAI3 and showing the pair is required for climbing-fiber synapse selection, answering how a single winner afferent is chosen and maintained.","evidence":"Genetic knockout, reciprocal binding assays, electrophysiology, and immunohistochemistry in mouse cerebellum, replicated across two labs","pmids":["25611509","25660030"],"confidence":"High","gaps":["Structural basis of C1QL1-BAI3 binding not resolved","Downstream intracellular signaling from BAI3 not defined","Whether the same axis operates outside cerebellum unknown"]},{"year":2009,"claim":"Showed C1QL1 pre-mRNA is subject to conserved A-to-I editing producing non-synonymous substitutions, raising the possibility of transcript-level functional diversification.","evidence":"RNA sequencing, comparative genomics, and RNA secondary-structure analysis across human, mouse, and zebrafish","pmids":["19275900"],"confidence":"Medium","gaps":["Functional consequence of edited residues on protein activity not tested","Tissue specificity and regulation of editing not established"]},{"year":2016,"claim":"Extended C1QL1 function beyond neurons by showing its globular domain drives angiogenesis through ERK1/2 signaling, hinting at BAI3 as a vascular receptor.","evidence":"HUVEC migration/tube-formation assays, phospho-ERK Western blots, U0126 inhibition, chick yolk sac membrane assay","pmids":["27734226"],"confidence":"Medium","gaps":["BAI3 involvement inferred from immunoreactivity only, not by loss-of-function","In vivo angiogenic role not demonstrated"]},{"year":2021,"claim":"Generalized the synapse-organizer role to the auditory periphery, showing C1QL1 in hair cells supports afferent synapse maintenance and nerve fiber innervation.","evidence":"Conditional and global knockout mice, ABR/DPOAE, confocal and electron microscopy, voltage-clamp recording","pmids":["33979385","34512267"],"confidence":"High","gaps":["Receptor mediating cochlear effects not identified in these studies","Conditional OHC KO lacked a compelling functional auditory phenotype"]},{"year":2022,"claim":"Probed non-neural physiology, implicating C1QL1 in ovarian folliculogenesis via granulosa cell autophagy/apoptosis while finding it largely dispensable for systemic metabolic homeostasis.","evidence":"Antibody-mediated blockade with hormone ELISA and IHC (ovary); constitutive KO with metabolic cage, body composition, and tolerance tests (metabolism)","pmids":["35560215","35403439"],"confidence":"Medium","gaps":["Ovarian effects rely on antibody blockade rather than genetic KO","Downstream signaling linking C1QL1 to autophagy/apoptosis not directly established","Receptor mediating reproductive and metabolic effects unknown"]},{"year":2023,"claim":"Placed C1QL1-BAI3 in a defined genetic hierarchy, showing it acts downstream of GluD2 to drive activity-dependent climbing-fiber reinnervation of mature dendrites.","evidence":"Viral overexpression, conditional knockout, electrophysiology, Ca2+ imaging, and GluD2 KO x Bai3 KO epistasis in mouse cerebellum","pmids":["37488606"],"confidence":"High","gaps":["Molecular link between GluD2 and C1QL1 upregulation not defined","How neuronal activity gates the reinnervation not resolved"]},{"year":2024,"claim":"Identified a glia-intrinsic function, showing C1QL1 bidirectionally controls oligodendrocyte progenitor differentiation and myelination in development and remyelination.","evidence":"OPC-specific conditional KO, in vivo viral overexpression, cuprizone demyelination model, and primary OPC culture with IHC","pmids":["39257292"],"confidence":"High","gaps":["Receptor and signaling pathway in OPCs not identified","Whether OPC effect is cell-autonomous via autocrine signaling unclear"]},{"year":2025,"claim":"Resolved the structural mechanism of receptor engagement, showing calcium-modulated hexamerization of the gC1q domain binds the BAI3 CUB domain and clusters receptors to scaffold synapses.","evidence":"Cryo-EM of the C1ql1 gC1q hexamer-BAI3 CUB complex, biochemical assembly assays, and cellular/in vivo validation","pmids":["41372137"],"confidence":"High","gaps":["How calcium concentration is sensed in the synaptic cleft in vivo not established","Stoichiometry of full-length linear clusters at native synapses not quantified"]},{"year":2025,"claim":"Connected the cochlear phenotype to a defined cytoskeletal effector pathway and uncovered an ER-localized, BAI3-independent function in cancer.","evidence":"Co-IP and colocalization with BAI3 plus pathway-component analysis (cochlea); LC-MS/MS, co-IP, methylation-specific PCR, and in vitro/in vivo apoptosis assays identifying HSP90alpha and VCP interactions (breast cancer)","pmids":["40193629","40583061"],"confidence":"Medium","gaps":["Cochlear pathway placement not validated by full genetic epistasis","ER-localization mechanism for a secreted protein not explained","Causality of HSP90alpha/VCP degradation in apoptosis partially inferred"]},{"year":2026,"claim":"Demonstrated pathological repurposing of the synapse-organizing axis, showing glioblastoma-secreted C1QL1 uses BAI3-RAC1 signaling to prune normal synapses and drive tumor microtube outgrowth.","evidence":"In vitro signaling assays, RAC1 inhibitor rescue, and in vivo glioma models with functional rescue experiments","pmids":["41747254"],"confidence":"Medium","gaps":["Pathway placement via inhibitor rather than genetic epistasis","Source and regulation of tumor C1QL1 expression not defined"]},{"year":null,"claim":"How the single C1QL1-BAI3 module is functionally specialized across such diverse contexts (cerebellum, cochlea, oligodendrocytes, vasculature, ovary, tumors) and which contexts engage BAI3 versus alternative receptors or intracellular partners remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying account of receptor choice across tissues","Intracellular ER-localized functions not reconciled with secreted synaptic role","Editing-dependent functional variation untested in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,10,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[10]}],"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":[10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,11,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12]}],"complexes":[],"partners":["BAI3","HSP90AA1","VCP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75973","full_name":"C1q-related factor","aliases":["C1q and tumor necrosis factor-related protein 14","C1q/TNF-related protein 14","Complement component 1 Q subcomponent-like 1"],"length_aa":258,"mass_kda":26.5,"function":"May regulate the number of excitatory synapses that are formed on hippocampus neurons. Has no effect on inhibitory synapses (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O75973/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QL1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C1QL1","total_profiled":1310},"omim":[{"mim_id":"615229","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 4; C1QL4","url":"https://www.omim.org/entry/615229"},{"mim_id":"615227","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 3; C1QL3","url":"https://www.omim.org/entry/615227"},{"mim_id":"614330","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 2; C1QL2","url":"https://www.omim.org/entry/614330"},{"mim_id":"614147","title":"C1q- AND TUMOR NECROSIS FACTOR-RELATED PROTEIN 8; C1QTNF8","url":"https://www.omim.org/entry/614147"},{"mim_id":"611586","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 1; C1QL1","url":"https://www.omim.org/entry/611586"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":41.9},{"tissue":"kidney","ntpm":17.1}],"url":"https://www.proteinatlas.org/search/C1QL1"},"hgnc":{"alias_symbol":["CRF","C1QRF","C1QTNF14","CTRP14"],"prev_symbol":[]},"alphafold":{"accession":"O75973","domains":[{"cath_id":"2.60.120.40","chopping":"129-258","consensus_level":"medium","plddt":95.0802,"start":129,"end":258}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75973","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75973-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75973-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QL1","jax_strain_url":"https://www.jax.org/strain/search?query=C1QL1"},"sequence":{"accession":"O75973","fasta_url":"https://rest.uniprot.org/uniprotkb/O75973.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75973/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75973"}},"corpus_meta":[{"pmid":"25611509","id":"PMC_25611509","title":"Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/25611509","citation_count":152,"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":"29321030","id":"PMC_29321030","title":"CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension.","date":"2018","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29321030","citation_count":30,"is_preprint":false},{"pmid":"27734226","id":"PMC_27734226","title":"C1ql1/Ctrp14 and C1ql4/Ctrp11 promote angiogenesis of endothelial cells through activation of ERK1/2 signal pathway.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27734226","citation_count":25,"is_preprint":false},{"pmid":"37488606","id":"PMC_37488606","title":"C1ql1-Bai3 signaling is necessary for climbing fiber synapse formation in mature Purkinje cells in coordination with neuronal activity.","date":"2023","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/37488606","citation_count":17,"is_preprint":false},{"pmid":"33979385","id":"PMC_33979385","title":"C1ql1 is expressed in adult outer hair cells of the cochlea in a tonotopic gradient.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33979385","citation_count":16,"is_preprint":false},{"pmid":"34512267","id":"PMC_34512267","title":"Deletion of C1ql1 Causes Hearing Loss and Abnormal Auditory Nerve Fibers in the Mouse Cochlea.","date":"2021","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34512267","citation_count":14,"is_preprint":false},{"pmid":"19275900","id":"PMC_19275900","title":"Conserved recoding RNA editing of vertebrate C1q-related factor C1QL1.","date":"2009","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/19275900","citation_count":13,"is_preprint":false},{"pmid":"35560215","id":"PMC_35560215","title":"Deficiency of C1QL1 Reduced Murine Ovarian Follicle Reserve Through Intraovarian and Endocrine Control.","date":"2022","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35560215","citation_count":12,"is_preprint":false},{"pmid":"35403439","id":"PMC_35403439","title":"CTRP14 inactivation alters physical activity and food intake response to fasting and refeeding.","date":"2022","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35403439","citation_count":11,"is_preprint":false},{"pmid":"39257292","id":"PMC_39257292","title":"C1ql1 expression in oligodendrocyte progenitor cells promotes oligodendrocyte differentiation.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/39257292","citation_count":10,"is_preprint":false},{"pmid":"37845276","id":"PMC_37845276","title":"Mapping and targeting of C1ql1-expressing cells in the mouse.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37845276","citation_count":9,"is_preprint":false},{"pmid":"40583061","id":"PMC_40583061","title":"C1QL1 inhibits breast cancer through the HSP90α/VCP-ERS/UPR axis.","date":"2025","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40583061","citation_count":3,"is_preprint":false},{"pmid":"36286293","id":"PMC_36286293","title":"C1QL1/CTRP14 Is Largely Dispensable for Atherosclerosis Formation in Apolipoprotein-E-Deficient Mice.","date":"2022","source":"Journal of cardiovascular development and disease","url":"https://pubmed.ncbi.nlm.nih.gov/36286293","citation_count":2,"is_preprint":false},{"pmid":"39761721","id":"PMC_39761721","title":"Role of CTRP14/C1QL1 in motor coordination and learning across the lifespan.","date":"2025","source":"Physiology & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/39761721","citation_count":1,"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":"40193629","id":"PMC_40193629","title":"C1QL1 regulates auditory nerve fibers growth via ELMO1-DOCK180-RAC1 integrin.","date":"2025","source":"Acta oto-laryngologica","url":"https://pubmed.ncbi.nlm.nih.gov/40193629","citation_count":1,"is_preprint":false},{"pmid":"41747254","id":"PMC_41747254","title":"Glioblastoma-Secreted C1QL1 Orchestrates Tumor Microtube Expansion and Neural Synaptic Pruning to Drive Malignant Synapse Formation and Recurrence.","date":"2026","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41747254","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11214,"output_tokens":3676,"usd":0.044391,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11428,"output_tokens":3824,"usd":0.07637,"stage2_stop_reason":"end_turn"},"total_usd":0.120761,"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\": 2015,\n      \"finding\": \"C1QL1 (provided by climbing fibers as an anterograde signal) specifically binds to BAI3 (brain-specific angiogenesis inhibitor 3), a cell-adhesion G-protein-coupled receptor expressed on postsynaptic Purkinje cells, and this C1QL1-BAI3 signaling is required to determine and maintain a single-winner climbing fiber in the mouse cerebellum throughout development and adulthood.\",\n      \"method\": \"Genetic knockout, binding assays, electrophysiology, immunohistochemistry\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated, loss-of-function with defined cellular phenotype, independently replicated across two labs in the same year\",\n      \"pmids\": [\"25611509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The C1QL1-BAI3 signaling pathway controls the stereotyped pattern of synaptic connectivity established by excitatory afferents (both climbing fibers and parallel fibers) on cerebellar Purkinje cells; restricted expression of C1QL1 in inferior olivary neurons ensures the proper synaptic territory for climbing fibers.\",\n      \"method\": \"Genetic knockout, overexpression, electrophysiology, immunohistochemistry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined synaptic phenotype, replicates and extends findings from concurrent independent lab\",\n      \"pmids\": [\"25660030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The globular domain of C1QL1/CTRP14 directly stimulates migration and capillary tube formation of HUVECs in a dose-dependent manner, activating phosphorylation of c-Raf, MEK1/2, ERK1/2, and p90RSK; MEK1/2 inhibition with U0126 blocks these effects. BAI3 immunoreactivity was detected in HUVECs, suggesting BAI3 mediates this proangiogenic effect.\",\n      \"method\": \"In vitro angiogenesis assay (HUVEC migration and tube formation), Western blot for phospho-ERK pathway components, pharmacological inhibition (U0126), chick yolk sac membrane assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional assays in one lab, BAI3 involvement inferred by immunoreactivity only (not proven by loss-of-function)\",\n      \"pmids\": [\"27734226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C1QL1 pre-mRNA undergoes A-to-I RNA editing in vivo, causing non-synonymous amino acid substitutions, conserved across human, mouse, and zebrafish; the major editing site had previously been misannotated as a SNP.\",\n      \"method\": \"RNA sequencing, comparative genomics, RNA secondary structure analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing of edited transcripts in multiple species with structural analysis, single lab\",\n      \"pmids\": [\"19275900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Overexpression of C1ql1 in climbing fibers or Bai3 in Purkinje cells causes transverse CF branches to elongate and form new synapses on distal dendrites of mature Purkinje cells; this reinnervation requires neuronal activity and is dependent on Bai3 in Purkinje cells. Additionally, C1ql1 levels in CFs are upregulated in GluD2 knockout mice, and the reinnervation phenotype of GluD2 KO is absent in Bai3 KO mice, placing C1ql1-Bai3 signaling downstream of GluD2-dependent synapse maintenance.\",\n      \"method\": \"Viral overexpression, conditional knockout, electrophysiology, Ca²⁺ imaging, immunohistochemistry, genetic epistasis (GluD2 KO × Bai3 KO double mutant)\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double-mutant analysis, multiple orthogonal methods (electrophysiology + imaging + IHC), activity-dependence validation\",\n      \"pmids\": [\"37488606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1ql1 is expressed in outer hair cells of the cochlea in an adolescence-onset, tonotopic gradient pattern. Conditional knockout of C1ql1 in outer hair cells results in histological evidence of reduced outer hair cell afferent synapse maintenance, though auditory behavioral and physiological phenotypes were not compelling.\",\n      \"method\": \"Fluorescent reporter knockin mouse, conditional knockout, histology/immunohistochemistry, auditory brainstem response testing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean conditional KO with histological readout but no significant functional phenotype, single lab\",\n      \"pmids\": [\"33979385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1ql1 global knockout mice exhibit progressive hearing loss with reduced auditory nerve fiber innervation of both inner and outer hair cells, and significant outer hair cell loss; however, spiral ganglion neurons are normal ultrastructurally, and IHC presynaptic machinery (synaptic vesicle release, presynaptic proteins) is not significantly affected by C1ql1 deletion.\",\n      \"method\": \"Global knockout mouse, auditory brainstem response, DPOAE, confocal microscopy, electron microscopy, voltage-clamp recording, immunocytochemistry\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, EM, confocal, ABR/DPOAE), clean KO with multiple specific phenotypic readouts\",\n      \"pmids\": [\"34512267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"C1QL1 deficiency in mice (via intraperitoneal and intrabursal injection of C1QL1 antiserum) impairs folliculogenesis, reduces granulosa cell autophagy, alleviates C1QL1-mediated inhibition of granulosa cell apoptosis, elevates circulating estradiol, reduces hypothalamic KISS1 and GnRH expression, and decreases serum FSH, leading to depletion of ovarian follicle reserve.\",\n      \"method\": \"Antibody-mediated blockade (IP + intrabursal injection), immunohistochemistry, ELISA for hormones, confocal microscopy for follicle staging\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple phenotypic readouts and pathway components examined but mechanism relies on antibody blockade (not genetic KO) and downstream signaling not directly linked\",\n      \"pmids\": [\"35560215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP14/C1QL1 deficiency in mice alters physical activity and food intake in a sex- and nutritional state-dependent manner (lower activity in fed males, increased activity in fasted/refed females, reduced food intake in refed males), but is largely dispensable for metabolic homeostasis, body composition, and insulin sensitivity.\",\n      \"method\": \"Constitutive knockout mouse, metabolic cage analysis (physical activity, food intake), body composition analysis, glucose tolerance test, insulin tolerance test, lipid profiling\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with multiple metabolic phenotypic readouts, single lab\",\n      \"pmids\": [\"35403439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1QL1 is expressed in oligodendrocyte progenitor cells (OPCs) and its deficiency (OPC-specific conditional KO) reduces OPC differentiation into oligodendrocytes and myelin production during development and after cuprizone-induced demyelination; conversely, in vivo overexpression of C1QL1 increases oligodendrocyte density and myelination during recovery. C1QL1 levels bidirectionally regulate OPC differentiation in primary culture.\",\n      \"method\": \"OPC-specific conditional knockout, in vivo viral overexpression, cuprizone demyelination model, primary OPC culture, immunohistochemistry\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional manipulation (KO + overexpression) with matching phenotypes in vivo and in vitro, clean cell-type-specific KO\",\n      \"pmids\": [\"39257292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The trimeric globular C1q (gC1q) domain of C1ql1 undergoes calcium-modulated domain-swapping to form a hexamer; cryo-EM 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 via the gC1q hexamer, providing a scaffold to accumulate BAI3 receptors on the plasma membrane, supporting synapse maintenance.\",\n      \"method\": \"Cryo-EM structure determination, biochemical assembly assays, computational analysis, cellular and in vivo functional validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with biochemical and in vivo validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"41372137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C1QL1 interacts with BAI3 in the cochlea (confirmed by colocalization and co-immunoprecipitation), and regulates auditory nerve fiber growth via the BAI3-ELMO1-DOCK180-RAC1 pathway; C1ql1 overexpression inhibits expression of the TIAM1-PARD3 pathway.\",\n      \"method\": \"Co-immunoprecipitation, colocalization imaging, overexpression/knockdown with pathway component analysis\",\n      \"journal\": \"Acta oto-laryngologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP confirms interaction in cochlea, pathway components measured but not fully validated by epistasis, single lab\",\n      \"pmids\": [\"40193629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In breast cancer, C1QL1 localizes to the endoplasmic reticulum and interacts with HSP90α and VCP (confirmed by co-immunoprecipitation and mass spectrometry), facilitating their ubiquitin-mediated degradation and thereby inducing ER stress/unfolded protein response (ERS/UPR) and caspase-dependent apoptosis. C1QL1 promoter methylation silences its expression in breast cancer.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, Western blot, overexpression/knockdown in vitro and in vivo (nude mice), flow cytometry (apoptosis/cell cycle), TUNEL, methylation-specific PCR\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and MS identify interactors, in vitro and in vivo functional readouts, single lab, mechanism partially inferred\",\n      \"pmids\": [\"40583061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Glioblastoma-secreted C1QL1 binds to BAI3 on neighboring neurons and GBM cells, activating RAC1-mediated cytoskeleton rearrangement to prune normal synapses and promote tumor microtube (TM) outgrowth and malignant synapse formation; a non-GEF-targeting RAC1 inhibitor rescues C1QL1-mediated synaptic pruning and inhibits glioma recurrence.\",\n      \"method\": \"In vitro signaling assays, pharmacological inhibition (RAC1 inhibitor), in vivo glioma models, functional rescue experiments\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with pharmacological rescue, single lab, pathway placement via inhibitor but not full genetic epistasis\",\n      \"pmids\": [\"41747254\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QL1 is a secreted trimeric C1q-family protein that, in its calcium-modulated hexameric form, binds the extracellular CUB domain of the adhesion-GPCR BAI3 to organize pre- and post-synaptic scaffolds; in the cerebellum it is transported anterogradely in climbing fiber axons to drive competitive synapse elimination and maintenance at the climbing fiber–Purkinje cell synapse, with downstream signaling proceeding through the BAI3-ELMO1-DOCK180-RAC1 cytoskeletal pathway, and it additionally promotes oligodendrocyte progenitor differentiation and myelination, regulates cochlear nerve fiber innervation, and in non-neural contexts can activate ERK1/2-dependent angiogenesis and modulate ER-stress-dependent apoptosis via interaction with HSP90α and VCP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QL1 is a secreted C1q-family protein that functions as a synaptic organizer by binding the adhesion-GPCR BAI3 to control the establishment, maintenance, and elimination of excitatory synapses in the nervous system [#0, #1]. In the cerebellum, C1QL1 is supplied as an anterograde signal by climbing fibers and acts on postsynaptic Purkinje cells to determine and maintain a single-winner climbing fiber, with its restricted expression in inferior olivary neurons defining the climbing-fiber synaptic territory [#0, #1]; this C1QL1-BAI3 axis operates downstream of GluD2-dependent synapse maintenance and drives activity-dependent reinnervation of mature Purkinje cell dendrites [#4]. Structurally, the trimeric globular gC1q domain undergoes calcium-modulated domain-swapping to assemble into a hexamer that engages the extended CUB domain of BAI3, and full-length C1QL1 forms linear clusters that accumulate BAI3 receptors at the plasma membrane to scaffold the synapse [#10]. Beyond the cerebellum, C1QL1 interacts with BAI3 in the cochlea to regulate auditory nerve fiber growth and hair-cell afferent innervation via the BAI3-ELMO1-DOCK180-RAC1 cytoskeletal pathway, with global loss causing progressive hearing loss [#6, #11], and it bidirectionally regulates oligodendrocyte progenitor differentiation and myelination during development and remyelination [#9]. In non-neural and disease contexts, the globular domain stimulates HUVEC migration and tube formation through ERK1/2 signaling [#2], C1QL1 localizes to the endoplasmic reticulum where it binds HSP90\\u03b1 and VCP to promote their degradation and induce ER-stress-dependent apoptosis in breast cancer [#12], and glioblastoma-secreted C1QL1 engages BAI3 to drive RAC1-mediated synaptic pruning and tumor microtube outgrowth [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established C1QL1's core function by identifying its receptor BAI3 and showing the pair is required for climbing-fiber synapse selection, answering how a single winner afferent is chosen and maintained.\",\n      \"evidence\": \"Genetic knockout, reciprocal binding assays, electrophysiology, and immunohistochemistry in mouse cerebellum, replicated across two labs\",\n      \"pmids\": [\"25611509\", \"25660030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of C1QL1-BAI3 binding not resolved\", \"Downstream intracellular signaling from BAI3 not defined\", \"Whether the same axis operates outside cerebellum unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed C1QL1 pre-mRNA is subject to conserved A-to-I editing producing non-synonymous substitutions, raising the possibility of transcript-level functional diversification.\",\n      \"evidence\": \"RNA sequencing, comparative genomics, and RNA secondary-structure analysis across human, mouse, and zebrafish\",\n      \"pmids\": [\"19275900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of edited residues on protein activity not tested\", \"Tissue specificity and regulation of editing not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended C1QL1 function beyond neurons by showing its globular domain drives angiogenesis through ERK1/2 signaling, hinting at BAI3 as a vascular receptor.\",\n      \"evidence\": \"HUVEC migration/tube-formation assays, phospho-ERK Western blots, U0126 inhibition, chick yolk sac membrane assay\",\n      \"pmids\": [\"27734226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BAI3 involvement inferred from immunoreactivity only, not by loss-of-function\", \"In vivo angiogenic role not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized the synapse-organizer role to the auditory periphery, showing C1QL1 in hair cells supports afferent synapse maintenance and nerve fiber innervation.\",\n      \"evidence\": \"Conditional and global knockout mice, ABR/DPOAE, confocal and electron microscopy, voltage-clamp recording\",\n      \"pmids\": [\"33979385\", \"34512267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating cochlear effects not identified in these studies\", \"Conditional OHC KO lacked a compelling functional auditory phenotype\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Probed non-neural physiology, implicating C1QL1 in ovarian folliculogenesis via granulosa cell autophagy/apoptosis while finding it largely dispensable for systemic metabolic homeostasis.\",\n      \"evidence\": \"Antibody-mediated blockade with hormone ELISA and IHC (ovary); constitutive KO with metabolic cage, body composition, and tolerance tests (metabolism)\",\n      \"pmids\": [\"35560215\", \"35403439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ovarian effects rely on antibody blockade rather than genetic KO\", \"Downstream signaling linking C1QL1 to autophagy/apoptosis not directly established\", \"Receptor mediating reproductive and metabolic effects unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed C1QL1-BAI3 in a defined genetic hierarchy, showing it acts downstream of GluD2 to drive activity-dependent climbing-fiber reinnervation of mature dendrites.\",\n      \"evidence\": \"Viral overexpression, conditional knockout, electrophysiology, Ca2+ imaging, and GluD2 KO x Bai3 KO epistasis in mouse cerebellum\",\n      \"pmids\": [\"37488606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between GluD2 and C1QL1 upregulation not defined\", \"How neuronal activity gates the reinnervation not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a glia-intrinsic function, showing C1QL1 bidirectionally controls oligodendrocyte progenitor differentiation and myelination in development and remyelination.\",\n      \"evidence\": \"OPC-specific conditional KO, in vivo viral overexpression, cuprizone demyelination model, and primary OPC culture with IHC\",\n      \"pmids\": [\"39257292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and signaling pathway in OPCs not identified\", \"Whether OPC effect is cell-autonomous via autocrine signaling unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the structural mechanism of receptor engagement, showing calcium-modulated hexamerization of the gC1q domain binds the BAI3 CUB domain and clusters receptors to scaffold synapses.\",\n      \"evidence\": \"Cryo-EM of the C1ql1 gC1q hexamer-BAI3 CUB complex, biochemical assembly assays, and cellular/in vivo validation\",\n      \"pmids\": [\"41372137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How calcium concentration is sensed in the synaptic cleft in vivo not established\", \"Stoichiometry of full-length linear clusters at native synapses not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected the cochlear phenotype to a defined cytoskeletal effector pathway and uncovered an ER-localized, BAI3-independent function in cancer.\",\n      \"evidence\": \"Co-IP and colocalization with BAI3 plus pathway-component analysis (cochlea); LC-MS/MS, co-IP, methylation-specific PCR, and in vitro/in vivo apoptosis assays identifying HSP90alpha and VCP interactions (breast cancer)\",\n      \"pmids\": [\"40193629\", \"40583061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cochlear pathway placement not validated by full genetic epistasis\", \"ER-localization mechanism for a secreted protein not explained\", \"Causality of HSP90alpha/VCP degradation in apoptosis partially inferred\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated pathological repurposing of the synapse-organizing axis, showing glioblastoma-secreted C1QL1 uses BAI3-RAC1 signaling to prune normal synapses and drive tumor microtube outgrowth.\",\n      \"evidence\": \"In vitro signaling assays, RAC1 inhibitor rescue, and in vivo glioma models with functional rescue experiments\",\n      \"pmids\": [\"41747254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway placement via inhibitor rather than genetic epistasis\", \"Source and regulation of tumor C1QL1 expression not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the single C1QL1-BAI3 module is functionally specialized across such diverse contexts (cerebellum, cochlea, oligodendrocytes, vasculature, ovary, tumors) and which contexts engage BAI3 versus alternative receptors or intracellular partners remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying account of receptor choice across tissues\", \"Intracellular ER-localized functions not reconciled with secreted synaptic role\", \"Editing-dependent functional variation untested in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 10, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BAI3\", \"HSP90AA1\", \"VCP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}