{"gene":"C1QL1","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2015,"finding":"C1QL1, a secreted complement C1Q-related protein expressed by climbing fibers (CFs), specifically binds to BAI3 (brain-specific angiogenesis inhibitor 3), an adhesion-GPCR expressed on postsynaptic Purkinje cells, functioning as an anterograde signal that determines and maintains the single-winner climbing fiber in the mouse cerebellum throughout development and adulthood.","method":"Co-IP/pulldown binding assays, genetic knockout mouse models, in vivo loss-of-function, behavioral assays (motor learning), immunohistochemistry, and cell-type-specific expression analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding demonstrated, genetic KO with defined cellular and behavioral phenotype, replicated across two independent papers in the same year","pmids":["25611509"],"is_preprint":false},{"year":2015,"finding":"The C1QL1–BAI3 signaling pathway controls the stereotyped pattern of connectivity established by excitatory afferents (both climbing fibers and parallel fibers) on cerebellar Purkinje cells; restricted and timely expression of C1QL1 in inferior olivary neurons ensures proper synaptic territory for climbing fibers, while BAI3 modulates synaptogenesis of both afferent types.","method":"Loss-of-function (genetic knockdown/knockout), immunofluorescence, electrophysiology, synapse morphology analysis in mouse cerebellum","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — clean KO/KD with defined synaptic phenotype, multiple orthogonal methods, consistent with Neuron 2015 findings","pmids":["25660030"],"is_preprint":false},{"year":2016,"finding":"C1QL1 (CTRP14) globular domain directly promotes migration and capillary tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner through activation of the c-Raf/MEK1/2/ERK1/2/p90RSK signaling cascade, an effect blocked by MEK1/2 inhibitor U0126; BAI3 immunoreactivity was detected in HUVECs, suggesting BAI3 mediates this proangiogenic activity.","method":"In vitro co-culture assay with recombinant C1QL1 protein, tube formation and migration assays, western blot for phospho-signaling intermediates, pharmacological inhibition (U0126), chick yolk sac membrane angiogenesis assay, immunohistochemistry for BAI3","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro reconstitution with defined signaling pathway and pharmacological validation, but single lab and receptor assignment to BAI3 is suggestive rather than definitive","pmids":["27734226"],"is_preprint":false}],"current_model":"C1QL1 is a secreted complement C1Q-family protein produced by climbing fiber neurons that acts as an anterograde synaptic organizer by binding to the adhesion-GPCR BAI3 on postsynaptic Purkinje cells, thereby determining and maintaining single-winner climbing fiber connectivity and regulating excitatory synapse formation in the cerebellum; additionally, its globular domain can promote angiogenesis via ERK1/2 signaling, potentially through BAI3 expressed on endothelial cells."},"narrative":{"teleology":[{"year":2015,"claim":"The identity of a trans-synaptic signal that instructs single-winner climbing fiber selection on Purkinje cells was unknown; two independent studies demonstrated that C1QL1, secreted by climbing fibers, binds the adhesion-GPCR BAI3 on Purkinje cells to determine and maintain mono-innervation, establishing C1QL1–BAI3 as the first anterograde organizer of climbing fiber connectivity.","evidence":"Co-IP/pulldown binding assays, C1ql1 knockout mice with electrophysiology and behavioral analysis, cell-type-specific expression mapping, and synapse morphology analysis in mouse cerebellum across two independent groups","pmids":["25611509","25660030"],"confidence":"High","gaps":["Structural basis of C1QL1–BAI3 interaction is unresolved","Downstream signaling cascades within Purkinje cells triggered by BAI3 engagement remain uncharacterized","Whether C1QL1 acts purely as a ligand or also modulates BAI3 cleavage or trafficking is unknown"]},{"year":2016,"claim":"Whether C1QL1 has functions outside synaptic organization was unclear; recombinant C1QL1 globular domain was shown to promote endothelial cell migration and tube formation via c-Raf/MEK1/2/ERK1/2 activation, extending its functional repertoire to proangiogenic signaling.","evidence":"In vitro HUVEC migration and tube formation assays with recombinant protein, western blot for phospho-ERK pathway, pharmacological inhibition with U0126, chick yolk sac angiogenesis assay","pmids":["27734226"],"confidence":"Medium","gaps":["BAI3 assignment as the endothelial receptor is based on immunodetection without loss-of-function validation","In vivo relevance of C1QL1-driven angiogenesis has not been demonstrated in mammalian models","Relationship between proangiogenic and synaptogenic functions is unexplored"]},{"year":null,"claim":"The intracellular signaling events downstream of BAI3 in Purkinje cells upon C1QL1 binding, the structural determinants of the C1QL1–BAI3 complex, and the physiological significance of C1QL1 proangiogenic activity in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of the C1QL1–BAI3 complex exists","Purkinje cell-intrinsic signaling downstream of BAI3 activation is unknown","Whether C1QL1 functions in other brain circuits beyond the olivocerebellar system has not been tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["ADGRB3"],"other_free_text":[]},"mechanistic_narrative":"C1QL1 is a secreted complement C1Q-family protein that functions as an anterograde synaptic organizer in the cerebellum by binding the adhesion-GPCR BAI3 on postsynaptic Purkinje cells, thereby determining and maintaining single-winner climbing fiber connectivity and regulating excitatory synapse territory throughout development and adulthood [PMID:25611509, PMID:25660030]. Restricted expression of C1QL1 in inferior olivary climbing fiber neurons ensures proper partitioning of synaptic territory between climbing fibers and parallel fibers on Purkinje cell dendrites [PMID:25660030]. The globular C1Q domain of C1QL1 also promotes endothelial cell migration and tube formation through activation of the c-Raf/MEK1/2/ERK1/2 signaling cascade [PMID:27734226]."},"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":"14744257","id":"PMC_14744257","title":"CRF and CRF receptors: role in stress responsivity and other behaviors.","date":"2004","source":"Annual review of pharmacology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/14744257","citation_count":1015,"is_preprint":false},{"pmid":"11064361","id":"PMC_11064361","title":"Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse.","date":"2000","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11064361","citation_count":859,"is_preprint":false},{"pmid":"11830263","id":"PMC_11830263","title":"The CRF peptide family and their receptors: yet more partners discovered.","date":"2002","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/11830263","citation_count":415,"is_preprint":false},{"pmid":"23939821","id":"PMC_23939821","title":"Key role of CRF in the skin stress response system.","date":"2013","source":"Endocrine reviews","url":"https://pubmed.ncbi.nlm.nih.gov/23939821","citation_count":326,"is_preprint":false},{"pmid":"20010888","id":"PMC_20010888","title":"The CRF system, stress, depression and anxiety-insights from human genetic studies.","date":"2009","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/20010888","citation_count":284,"is_preprint":false},{"pmid":"16918397","id":"PMC_16918397","title":"Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets.","date":"2006","source":"CNS & neurological disorders drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/16918397","citation_count":253,"is_preprint":false},{"pmid":"8257022","id":"PMC_8257022","title":"Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress.","date":"1993","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8257022","citation_count":238,"is_preprint":false},{"pmid":"3003585","id":"PMC_3003585","title":"Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer's disease.","date":"1986","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/3003585","citation_count":233,"is_preprint":false},{"pmid":"10375459","id":"PMC_10375459","title":"Evolution and physiology of the corticotropin-releasing factor (CRF) family of neuropeptides in vertebrates.","date":"1999","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10375459","citation_count":225,"is_preprint":false},{"pmid":"19912996","id":"PMC_19912996","title":"The role of CRF and CRF-related peptides in the dark side of addiction.","date":"2009","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/19912996","citation_count":208,"is_preprint":false},{"pmid":"17403068","id":"PMC_17403068","title":"Increased drinking during withdrawal from intermittent ethanol exposure is blocked by the CRF receptor antagonist D-Phe-CRF(12-41).","date":"2007","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/17403068","citation_count":186,"is_preprint":false},{"pmid":"2982594","id":"PMC_2982594","title":"Regulation of corticotropin-releasing factor (CRF) receptors in the rat pituitary gland: effects of adrenalectomy on CRF receptors and corticotroph responses.","date":"1985","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/2982594","citation_count":169,"is_preprint":false},{"pmid":"19906236","id":"PMC_19906236","title":"Role of CRF receptor signaling in stress vulnerability, anxiety, and depression.","date":"2009","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19906236","citation_count":167,"is_preprint":false},{"pmid":"16423710","id":"PMC_16423710","title":"Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety.","date":"2005","source":"Stress (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/16423710","citation_count":167,"is_preprint":false},{"pmid":"16403502","id":"PMC_16403502","title":"CRF and stress in fish.","date":"2006","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/16403502","citation_count":167,"is_preprint":false},{"pmid":"31323874","id":"PMC_31323874","title":"A Narrative Review of Cancer-Related Fatigue (CRF) and Its Possible Pathogenesis.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31323874","citation_count":165,"is_preprint":false},{"pmid":"24270188","id":"PMC_24270188","title":"Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway.","date":"2013","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24270188","citation_count":165,"is_preprint":false},{"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":151,"is_preprint":false},{"pmid":"12361401","id":"PMC_12361401","title":"Potent and long-acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists.","date":"2002","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12361401","citation_count":147,"is_preprint":false},{"pmid":"15337374","id":"PMC_15337374","title":"Interactions between NPY and CRF in the amygdala to regulate emotionality.","date":"2004","source":"Neuropeptides","url":"https://pubmed.ncbi.nlm.nih.gov/15337374","citation_count":138,"is_preprint":false},{"pmid":"9528930","id":"PMC_9528930","title":"Effects of leptin on corticotropin-releasing factor (CRF) synthesis and CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ob) mice.","date":"1998","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9528930","citation_count":132,"is_preprint":false},{"pmid":"28265716","id":"PMC_28265716","title":"Don't stress about CRF: assessing the translational failures of CRF1antagonists.","date":"2017","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28265716","citation_count":131,"is_preprint":false},{"pmid":"28260504","id":"PMC_28260504","title":"The CRF Family of Neuropeptides and their Receptors - Mediators of the Central Stress Response.","date":"2018","source":"Current molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28260504","citation_count":115,"is_preprint":false},{"pmid":"20130533","id":"PMC_20130533","title":"CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis.","date":"2010","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20130533","citation_count":113,"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":111,"is_preprint":false},{"pmid":"12915052","id":"PMC_12915052","title":"Nibbling at CRF receptor control of feeding and gastrocolonic motility.","date":"2003","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12915052","citation_count":102,"is_preprint":false},{"pmid":"19843974","id":"PMC_19843974","title":"Corticotropin-releasing factor (CRF) sensitization of ethanol withdrawal-induced anxiety-like behavior is brain site specific and mediated by CRF-1 receptors: relation to stress-induced sensitization.","date":"2009","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/19843974","citation_count":91,"is_preprint":false},{"pmid":"23754975","id":"PMC_23754975","title":"The CRF system and social behavior: a review.","date":"2013","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23754975","citation_count":89,"is_preprint":false},{"pmid":"12845406","id":"PMC_12845406","title":"Role of corticotropin releasing factor (CRF) receptors 1 and 2 in CRF-potentiated acoustic startle in mice.","date":"2003","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12845406","citation_count":88,"is_preprint":false},{"pmid":"21813699","id":"PMC_21813699","title":"Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21813699","citation_count":88,"is_preprint":false},{"pmid":"19800323","id":"PMC_19800323","title":"A ventral tegmental CRF-glutamate-dopamine interaction in addiction.","date":"2009","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/19800323","citation_count":87,"is_preprint":false},{"pmid":"22363652","id":"PMC_22363652","title":"Ghrelin indirectly activates hypophysiotropic CRF neurons in rodents.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22363652","citation_count":86,"is_preprint":false},{"pmid":"11222989","id":"PMC_11222989","title":"Role of CRF receptor 1 in central CRF-induced stimulation of colonic propulsion in rats.","date":"2001","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/11222989","citation_count":84,"is_preprint":false},{"pmid":"15701705","id":"PMC_15701705","title":"A soluble mouse brain splice variant of type 2alpha corticotropin-releasing factor (CRF) receptor binds ligands and modulates their activity.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15701705","citation_count":82,"is_preprint":false},{"pmid":"27428651","id":"PMC_27428651","title":"Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics.","date":"2016","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27428651","citation_count":82,"is_preprint":false},{"pmid":"24672423","id":"PMC_24672423","title":"CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress.","date":"2014","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24672423","citation_count":81,"is_preprint":false},{"pmid":"18171711","id":"PMC_18171711","title":"Pro- and anti-nociceptive effects of corticotropin-releasing factor (CRF) in central amygdala neurons are mediated through different receptors.","date":"2008","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/18171711","citation_count":81,"is_preprint":false},{"pmid":"16339088","id":"PMC_16339088","title":"Cortical sources of CRF, NKB, and CCK and their effects on pyramidal cells in the neocortex.","date":"2005","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/16339088","citation_count":80,"is_preprint":false},{"pmid":"2826113","id":"PMC_2826113","title":"Corticotropin-releasing factor (CRF) induces desensitization of the rat pituitary CRF receptor-adenylate cyclase complex.","date":"1988","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/2826113","citation_count":80,"is_preprint":false},{"pmid":"8411001","id":"PMC_8411001","title":"Synthesis and relative potencies of new constrained CRF antagonists.","date":"1993","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8411001","citation_count":77,"is_preprint":false},{"pmid":"17216263","id":"PMC_17216263","title":"Nutrition in children with CRF and on dialysis.","date":"2007","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/17216263","citation_count":72,"is_preprint":false},{"pmid":"10198329","id":"PMC_10198329","title":"Peripheral urocortin delays gastric emptying: role of CRF receptor 2.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10198329","citation_count":71,"is_preprint":false},{"pmid":"14742649","id":"PMC_14742649","title":"Biting suppresses stress-induced expression of corticotropin-releasing factor (CRF) in the rat hypothalamus.","date":"2004","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/14742649","citation_count":70,"is_preprint":false},{"pmid":"15974983","id":"PMC_15974983","title":"The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications.","date":"2005","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15974983","citation_count":68,"is_preprint":false},{"pmid":"23657440","id":"PMC_23657440","title":"CRF mediates the anxiogenic and anti-rewarding, but not the anorectic effects of PACAP.","date":"2013","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23657440","citation_count":68,"is_preprint":false},{"pmid":"12397512","id":"PMC_12397512","title":"A role for corticotropin releasing factor (CRF) in ethanol consumption, sensitivity, and reward as revealed by CRF-deficient mice.","date":"2002","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12397512","citation_count":67,"is_preprint":false},{"pmid":"11960782","id":"PMC_11960782","title":"Peripheral CRF activates myenteric neurons in the proximal colon through CRF(1) receptor in conscious rats.","date":"2002","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11960782","citation_count":66,"is_preprint":false},{"pmid":"19675537","id":"PMC_19675537","title":"Stress-induced potentiation of cocaine reward: a role for CRF R1 and CREB.","date":"2009","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19675537","citation_count":65,"is_preprint":false},{"pmid":"12941376","id":"PMC_12941376","title":"Corticotropin-releasing factor (CRF) and related peptides confer neuroprotection via type 1 CRF receptors.","date":"2003","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12941376","citation_count":64,"is_preprint":false},{"pmid":"12110614","id":"PMC_12110614","title":"The highly selective CRF(2) receptor antagonist K41498 binds to presynaptic CRF(2) receptors in rat brain.","date":"2002","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12110614","citation_count":64,"is_preprint":false},{"pmid":"10519912","id":"PMC_10519912","title":"Actions of CRF and its analogs.","date":"1999","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10519912","citation_count":59,"is_preprint":false},{"pmid":"19891960","id":"PMC_19891960","title":"Convergent actions of orexin/hypocretin and CRF on dopamine neurons: Emerging players in addiction.","date":"2009","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/19891960","citation_count":59,"is_preprint":false},{"pmid":"21382355","id":"PMC_21382355","title":"Hypothalamic oxytocin attenuates CRF expression via GABA(A) receptors in rats.","date":"2011","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/21382355","citation_count":58,"is_preprint":false},{"pmid":"19078950","id":"PMC_19078950","title":"Differential effects of the CRF-R1 antagonist GSK876008 on fear-potentiated, light- and CRF-enhanced startle suggest preferential involvement in sustained vs phasic threat responses.","date":"2008","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19078950","citation_count":58,"is_preprint":false},{"pmid":"9873487","id":"PMC_9873487","title":"Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists.","date":"1998","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/9873487","citation_count":57,"is_preprint":false},{"pmid":"8597429","id":"PMC_8597429","title":"Behavioral, neurochemical, and immunological responses to CRF administration. Is CRF a mediator of stress?","date":"1995","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8597429","citation_count":57,"is_preprint":false},{"pmid":"20201818","id":"PMC_20201818","title":"Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism.","date":"2010","source":"CNS & neurological disorders drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/20201818","citation_count":56,"is_preprint":false},{"pmid":"20234885","id":"PMC_20234885","title":"Emerging role of alternative splicing of CRF1 receptor in CRF signaling.","date":"2010","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/20234885","citation_count":55,"is_preprint":false},{"pmid":"21540451","id":"PMC_21540451","title":"Urocortin 1 reduces food intake and ghrelin secretion via CRF(2) receptors.","date":"2011","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21540451","citation_count":55,"is_preprint":false},{"pmid":"29056150","id":"PMC_29056150","title":"Substance P and the Neurokinin-1 Receptor: The New CRF.","date":"2017","source":"International review of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29056150","citation_count":54,"is_preprint":false},{"pmid":"17453142","id":"PMC_17453142","title":"The corticotropin-releasing factor (CRF) family of peptides as local modulators of adrenal function.","date":"2007","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/17453142","citation_count":53,"is_preprint":false},{"pmid":"16878401","id":"PMC_16878401","title":"Regulation of synaptic transmission by CRF receptors.","date":"2006","source":"Reviews in the neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/16878401","citation_count":53,"is_preprint":false},{"pmid":"16614059","id":"PMC_16614059","title":"Expression of corticotropin-releasing factor and CRF receptors in micturition pathways after cyclophosphamide-induced cystitis.","date":"2006","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16614059","citation_count":51,"is_preprint":false},{"pmid":"24076419","id":"PMC_24076419","title":"Evolution and phylogeny of the corticotropin-releasing factor (CRF) family of peptides: expansion and specialization in the vertebrates.","date":"2013","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/24076419","citation_count":50,"is_preprint":false},{"pmid":"19749107","id":"PMC_19749107","title":"Functional differences between two CRF-related diuretic hormone receptors in Drosophila.","date":"2009","source":"The Journal of experimental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19749107","citation_count":50,"is_preprint":false},{"pmid":"12529934","id":"PMC_12529934","title":"Pharmacology and biology of corticotropin-releasing factor (CRF) receptors.","date":"2002","source":"Receptors & channels","url":"https://pubmed.ncbi.nlm.nih.gov/12529934","citation_count":49,"is_preprint":false},{"pmid":"17296558","id":"PMC_17296558","title":"Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/17296558","citation_count":49,"is_preprint":false},{"pmid":"28830762","id":"PMC_28830762","title":"Contribution of amygdala CRF neurons to chronic pain.","date":"2017","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28830762","citation_count":48,"is_preprint":false},{"pmid":"10411571","id":"PMC_10411571","title":"Peripheral injection of a new corticotropin-releasing factor (CRF) antagonist, astressin, blocks peripheral CRF- and abdominal surgery-induced delayed gastric emptying in rats.","date":"1999","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/10411571","citation_count":48,"is_preprint":false},{"pmid":"15899517","id":"PMC_15899517","title":"Listening to mutant mice: a spotlight on the role of CRF/CRF receptor systems in affective disorders.","date":"2005","source":"Neuroscience and biobehavioral reviews","url":"https://pubmed.ncbi.nlm.nih.gov/15899517","citation_count":47,"is_preprint":false},{"pmid":"8415932","id":"PMC_8415932","title":"Amygdala kindling, anxiety, and corticotrophin releasing factor (CRF).","date":"1993","source":"Physiology & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/8415932","citation_count":47,"is_preprint":false},{"pmid":"7783417","id":"PMC_7783417","title":"Down-regulation of PTH-PTHrP receptor of heart in CRF: role of [Ca2+]i.","date":"1995","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/7783417","citation_count":46,"is_preprint":false},{"pmid":"12603831","id":"PMC_12603831","title":"Corticotropin-releasing factor (CRF) rapidly suppresses apoptosis by acting upstream of the activation of caspases.","date":"2003","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12603831","citation_count":46,"is_preprint":false},{"pmid":"8907325","id":"PMC_8907325","title":"Expression of ionotropic glutamate receptor subunit mRNAs by paraventricular corticotropin-releasing factor (CRF) neurons.","date":"1996","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/8907325","citation_count":45,"is_preprint":false},{"pmid":"18955037","id":"PMC_18955037","title":"Proximal colon distension induces Fos expression in oxytocin-, vasopressin-, CRF- and catecholamines-containing neurons in rat brain.","date":"2008","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/18955037","citation_count":44,"is_preprint":false},{"pmid":"21684787","id":"PMC_21684787","title":"Experimental neuropathy increases limbic forebrain CRF.","date":"2012","source":"European journal of pain (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21684787","citation_count":40,"is_preprint":false},{"pmid":"16633893","id":"PMC_16633893","title":"Corticotropin Releasing Factor (CRF) activation of NF-kappaB-directed transcription in leukocytes.","date":"2006","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/16633893","citation_count":39,"is_preprint":false},{"pmid":"8636316","id":"PMC_8636316","title":"High levels of corticotropin-releasing factor (CRF) are inversely correlated with low levels of maternal CRF-binding protein in pregnant women with pregnancy-induced hypertension.","date":"1996","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/8636316","citation_count":38,"is_preprint":false},{"pmid":"27818644","id":"PMC_27818644","title":"An Update on CRF Mechanisms Underlying Alcohol Use Disorders and Dependence.","date":"2016","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27818644","citation_count":37,"is_preprint":false},{"pmid":"17188689","id":"PMC_17188689","title":"Involvement of the corticotropin-releasing factor (CRF) type 2 receptor in CRF-induced thyrotropin release by the amphibian pituitary gland.","date":"2006","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17188689","citation_count":37,"is_preprint":false},{"pmid":"20699230","id":"PMC_20699230","title":"VIP, CRF, and PACAP act at distinct receptors to elicit different cAMP/PKA dynamics in the neocortex.","date":"2010","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/20699230","citation_count":37,"is_preprint":false},{"pmid":"12413940","id":"PMC_12413940","title":"GRK3 regulation during CRF- and urocortin-induced CRF1 receptor desensitization.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12413940","citation_count":35,"is_preprint":false},{"pmid":"10497910","id":"PMC_10497910","title":"Characterisation using microphysiometry of CRF receptor pharmacology.","date":"1999","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/10497910","citation_count":35,"is_preprint":false},{"pmid":"30651328","id":"PMC_30651328","title":"Prefrontal Corticotropin-Releasing Factor (CRF) Neurons Act Locally to Modulate Frontostriatal Cognition and Circuit Function.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30651328","citation_count":35,"is_preprint":false},{"pmid":"9449637","id":"PMC_9449637","title":"Corticotropin-releasing factor (CRF) agonists stimulate testosterone production in mouse leydig cells through CRF receptor-1.","date":"1998","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9449637","citation_count":34,"is_preprint":false},{"pmid":"16284082","id":"PMC_16284082","title":"Peripherally administered CRF stimulates colonic motility via central CRF receptors and vagal pathways in conscious rats.","date":"2005","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16284082","citation_count":32,"is_preprint":false},{"pmid":"29374836","id":"PMC_29374836","title":"Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking.","date":"2018","source":"Handbook of experimental pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29374836","citation_count":31,"is_preprint":false},{"pmid":"23362976","id":"PMC_23362976","title":"Intermittent access ethanol consumption dysregulates CRF function in the hypothalamus and is attenuated by the CRF-R1 antagonist, CP-376395.","date":"2013","source":"Addiction biology","url":"https://pubmed.ncbi.nlm.nih.gov/23362976","citation_count":31,"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":"23893957","id":"PMC_23893957","title":"miR-449a contributes to glucocorticoid-induced CRF-R1 downregulation in the pituitary during stress.","date":"2013","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/23893957","citation_count":30,"is_preprint":false},{"pmid":"9348205","id":"PMC_9348205","title":"Regulation of corticotropin-releasing factor (CRF) messenger ribonucleic acid and CRF peptide in the amygdala: studies in primary amygdalar cultures.","date":"1997","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9348205","citation_count":30,"is_preprint":false},{"pmid":"23590881","id":"PMC_23590881","title":"Corticotropin-releasing factor (CRF) and α 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats.","date":"2013","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23590881","citation_count":30,"is_preprint":false},{"pmid":"17716630","id":"PMC_17716630","title":"CRF1 not glucocorticoid receptors mediate prepulse inhibition deficits in mice overexpressing CRF.","date":"2007","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/17716630","citation_count":30,"is_preprint":false},{"pmid":"26611915","id":"PMC_26611915","title":"Endogenous CRF in rat large intestine mediates motor and secretory responses to stress.","date":"2015","source":"Neurogastroenterology and motility","url":"https://pubmed.ncbi.nlm.nih.gov/26611915","citation_count":28,"is_preprint":false},{"pmid":"21568890","id":"PMC_21568890","title":"Members of CRF family and their receptors: from past to future.","date":"2011","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21568890","citation_count":27,"is_preprint":false},{"pmid":"25340785","id":"PMC_25340785","title":"Grin1 receptor deletion within CRF neurons enhances fear memory.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25340785","citation_count":26,"is_preprint":false},{"pmid":"11730708","id":"PMC_11730708","title":"Electrophysiological effects of sustained delivery of CRF and its receptor agonists in hippocampal slices.","date":"2001","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/11730708","citation_count":26,"is_preprint":false},{"pmid":"21683135","id":"PMC_21683135","title":"Effects of citalopram on serotonin and CRF systems in the midbrain of primates with differences in stress sensitivity.","date":"2011","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/21683135","citation_count":25,"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":"18234674","id":"PMC_18234674","title":"Residues of corticotropin releasing factor-binding protein (CRF-BP) that selectively abrogate binding to CRF but not to urocortin 1.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18234674","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52733,"output_tokens":958,"usd":0.086285},"stage2":{"model":"claude-opus-4-6","input_tokens":4143,"output_tokens":1189,"usd":0.07566},"total_usd":0.161945,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"C1QL1, a secreted complement C1Q-related protein expressed by climbing fibers (CFs), specifically binds to BAI3 (brain-specific angiogenesis inhibitor 3), an adhesion-GPCR expressed on postsynaptic Purkinje cells, functioning as an anterograde signal that determines and maintains the single-winner climbing fiber in the mouse cerebellum throughout development and adulthood.\",\n      \"method\": \"Co-IP/pulldown binding assays, genetic knockout mouse models, in vivo loss-of-function, behavioral assays (motor learning), immunohistochemistry, and cell-type-specific expression analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding demonstrated, genetic KO with defined cellular and behavioral phenotype, replicated across two independent papers 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 connectivity established by excitatory afferents (both climbing fibers and parallel fibers) on cerebellar Purkinje cells; restricted and timely expression of C1QL1 in inferior olivary neurons ensures proper synaptic territory for climbing fibers, while BAI3 modulates synaptogenesis of both afferent types.\",\n      \"method\": \"Loss-of-function (genetic knockdown/knockout), immunofluorescence, electrophysiology, synapse morphology analysis in mouse cerebellum\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined synaptic phenotype, multiple orthogonal methods, consistent with Neuron 2015 findings\",\n      \"pmids\": [\"25660030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C1QL1 (CTRP14) globular domain directly promotes migration and capillary tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner through activation of the c-Raf/MEK1/2/ERK1/2/p90RSK signaling cascade, an effect blocked by MEK1/2 inhibitor U0126; BAI3 immunoreactivity was detected in HUVECs, suggesting BAI3 mediates this proangiogenic activity.\",\n      \"method\": \"In vitro co-culture assay with recombinant C1QL1 protein, tube formation and migration assays, western blot for phospho-signaling intermediates, pharmacological inhibition (U0126), chick yolk sac membrane angiogenesis assay, immunohistochemistry for BAI3\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro reconstitution with defined signaling pathway and pharmacological validation, but single lab and receptor assignment to BAI3 is suggestive rather than definitive\",\n      \"pmids\": [\"27734226\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QL1 is a secreted complement C1Q-family protein produced by climbing fiber neurons that acts as an anterograde synaptic organizer by binding to the adhesion-GPCR BAI3 on postsynaptic Purkinje cells, thereby determining and maintaining single-winner climbing fiber connectivity and regulating excitatory synapse formation in the cerebellum; additionally, its globular domain can promote angiogenesis via ERK1/2 signaling, potentially through BAI3 expressed on endothelial cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"C1QL1 is a secreted complement C1Q-family protein that functions as an anterograde synaptic organizer in the cerebellum by binding the adhesion-GPCR BAI3 on postsynaptic Purkinje cells, thereby determining and maintaining single-winner climbing fiber connectivity and regulating excitatory synapse territory throughout development and adulthood [PMID:25611509, PMID:25660030]. Restricted expression of C1QL1 in inferior olivary climbing fiber neurons ensures proper partitioning of synaptic territory between climbing fibers and parallel fibers on Purkinje cell dendrites [PMID:25660030]. The globular C1Q domain of C1QL1 also promotes endothelial cell migration and tube formation through activation of the c-Raf/MEK1/2/ERK1/2 signaling cascade [PMID:27734226].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"The identity of a trans-synaptic signal that instructs single-winner climbing fiber selection on Purkinje cells was unknown; two independent studies demonstrated that C1QL1, secreted by climbing fibers, binds the adhesion-GPCR BAI3 on Purkinje cells to determine and maintain mono-innervation, establishing C1QL1–BAI3 as the first anterograde organizer of climbing fiber connectivity.\",\n      \"evidence\": \"Co-IP/pulldown binding assays, C1ql1 knockout mice with electrophysiology and behavioral analysis, cell-type-specific expression mapping, and synapse morphology analysis in mouse cerebellum across two independent groups\",\n      \"pmids\": [\"25611509\", \"25660030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of C1QL1–BAI3 interaction is unresolved\",\n        \"Downstream signaling cascades within Purkinje cells triggered by BAI3 engagement remain uncharacterized\",\n        \"Whether C1QL1 acts purely as a ligand or also modulates BAI3 cleavage or trafficking is unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether C1QL1 has functions outside synaptic organization was unclear; recombinant C1QL1 globular domain was shown to promote endothelial cell migration and tube formation via c-Raf/MEK1/2/ERK1/2 activation, extending its functional repertoire to proangiogenic signaling.\",\n      \"evidence\": \"In vitro HUVEC migration and tube formation assays with recombinant protein, western blot for phospho-ERK pathway, pharmacological inhibition with U0126, chick yolk sac angiogenesis assay\",\n      \"pmids\": [\"27734226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"BAI3 assignment as the endothelial receptor is based on immunodetection without loss-of-function validation\",\n        \"In vivo relevance of C1QL1-driven angiogenesis has not been demonstrated in mammalian models\",\n        \"Relationship between proangiogenic and synaptogenic functions is unexplored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling events downstream of BAI3 in Purkinje cells upon C1QL1 binding, the structural determinants of the C1QL1–BAI3 complex, and the physiological significance of C1QL1 proangiogenic activity in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of the C1QL1–BAI3 complex exists\",\n        \"Purkinje cell-intrinsic signaling downstream of BAI3 activation is unknown\",\n        \"Whether C1QL1 functions in other brain circuits beyond the olivocerebellar system has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ADGRB3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}