Affinage

C1QL1

C1q-related factor · UniProt O75973

Length
258 aa
Mass
26.5 kDa
Annotated
2026-04-28
100 papers in source corpus 3 papers cited in narrative 3 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2015 High

    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

    PMID:25611509 PMID:25660030

    Open questions at the time
    • 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
  2. 2016 Medium

    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

    PMID:27734226

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 1
Partners
ADGRB3

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 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. 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 Neuron High 25611509
2015 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. Loss-of-function (genetic knockdown/knockout), immunofluorescence, electrophysiology, synapse morphology analysis in mouse cerebellum Cell reports High 25660030
2016 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. 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 Molecular and cellular biochemistry Medium 27734226

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 CRF and CRF receptors: role in stress responsivity and other behaviors. Annual review of pharmacology and toxicology 1015 14744257
2000 Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. The Journal of comparative neurology 859 11064361
2002 The CRF peptide family and their receptors: yet more partners discovered. Trends in pharmacological sciences 415 11830263
2013 Key role of CRF in the skin stress response system. Endocrine reviews 326 23939821
2009 The CRF system, stress, depression and anxiety-insights from human genetic studies. Molecular psychiatry 284 20010888
2006 Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS & neurological disorders drug targets 253 16918397
1993 Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress. Annals of the New York Academy of Sciences 238 8257022
1986 Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer's disease. Nature 233 3003585
1999 Evolution and physiology of the corticotropin-releasing factor (CRF) family of neuropeptides in vertebrates. General and comparative endocrinology 225 10375459
2009 The role of CRF and CRF-related peptides in the dark side of addiction. Brain research 208 19912996
2007 Increased drinking during withdrawal from intermittent ethanol exposure is blocked by the CRF receptor antagonist D-Phe-CRF(12-41). Alcoholism, clinical and experimental research 186 17403068
1985 Regulation of corticotropin-releasing factor (CRF) receptors in the rat pituitary gland: effects of adrenalectomy on CRF receptors and corticotroph responses. Endocrinology 169 2982594
2009 Role of CRF receptor signaling in stress vulnerability, anxiety, and depression. Annals of the New York Academy of Sciences 167 19906236
2006 CRF and stress in fish. General and comparative endocrinology 167 16403502
2005 Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety. Stress (Amsterdam, Netherlands) 167 16423710
2019 A Narrative Review of Cancer-Related Fatigue (CRF) and Its Possible Pathogenesis. Cells 165 31323874
2013 Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nature neuroscience 165 24270188
2015 Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. Neuron 151 25611509
2002 Potent and long-acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists. Journal of medicinal chemistry 147 12361401
2004 Interactions between NPY and CRF in the amygdala to regulate emotionality. Neuropeptides 138 15337374
1998 Effects of leptin on corticotropin-releasing factor (CRF) synthesis and CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ob) mice. Endocrinology 132 9528930
2017 Don't stress about CRF: assessing the translational failures of CRF1antagonists. Psychopharmacology 131 28265716
2018 The CRF Family of Neuropeptides and their Receptors - Mediators of the Central Stress Response. Current molecular pharmacology 115 28260504
2010 CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 113 20130533
2015 The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells. Cell reports 111 25660030
2003 Nibbling at CRF receptor control of feeding and gastrocolonic motility. Trends in pharmacological sciences 102 12915052
2009 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. The Journal of pharmacology and experimental therapeutics 91 19843974
2013 The CRF system and social behavior: a review. Frontiers in neuroscience 89 23754975
2011 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. The Journal of neuroscience : the official journal of the Society for Neuroscience 88 21813699
2003 Role of corticotropin releasing factor (CRF) receptors 1 and 2 in CRF-potentiated acoustic startle in mice. Psychopharmacology 88 12845406
2009 A ventral tegmental CRF-glutamate-dopamine interaction in addiction. Brain research 87 19800323
2012 Ghrelin indirectly activates hypophysiotropic CRF neurons in rodents. PloS one 86 22363652
2001 Role of CRF receptor 1 in central CRF-induced stimulation of colonic propulsion in rats. Brain research 84 11222989
2016 Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics. Nature neuroscience 82 27428651
2005 A soluble mouse brain splice variant of type 2alpha corticotropin-releasing factor (CRF) receptor binds ligands and modulates their activity. Proceedings of the National Academy of Sciences of the United States of America 82 15701705
2014 CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress. Frontiers in neuroscience 81 24672423
2008 Pro- and anti-nociceptive effects of corticotropin-releasing factor (CRF) in central amygdala neurons are mediated through different receptors. Journal of neurophysiology 81 18171711
2005 Cortical sources of CRF, NKB, and CCK and their effects on pyramidal cells in the neocortex. Cerebral cortex (New York, N.Y. : 1991) 80 16339088
1988 Corticotropin-releasing factor (CRF) induces desensitization of the rat pituitary CRF receptor-adenylate cyclase complex. Endocrinology 80 2826113
1993 Synthesis and relative potencies of new constrained CRF antagonists. Journal of medicinal chemistry 77 8411001
2007 Nutrition in children with CRF and on dialysis. Pediatric nephrology (Berlin, Germany) 72 17216263
1999 Peripheral urocortin delays gastric emptying: role of CRF receptor 2. The American journal of physiology 71 10198329
2004 Biting suppresses stress-induced expression of corticotropin-releasing factor (CRF) in the rat hypothalamus. Journal of dental research 70 14742649
2013 CRF mediates the anxiogenic and anti-rewarding, but not the anorectic effects of PACAP. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 68 23657440
2005 The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. Current medicinal chemistry 68 15974983
2002 A role for corticotropin releasing factor (CRF) in ethanol consumption, sensitivity, and reward as revealed by CRF-deficient mice. Psychopharmacology 67 12397512
2002 Peripheral CRF activates myenteric neurons in the proximal colon through CRF(1) receptor in conscious rats. American journal of physiology. Gastrointestinal and liver physiology 66 11960782
2009 Stress-induced potentiation of cocaine reward: a role for CRF R1 and CREB. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 65 19675537
2003 Corticotropin-releasing factor (CRF) and related peptides confer neuroprotection via type 1 CRF receptors. Neuropharmacology 64 12941376
2002 The highly selective CRF(2) receptor antagonist K41498 binds to presynaptic CRF(2) receptors in rat brain. British journal of pharmacology 64 12110614
2009 Convergent actions of orexin/hypocretin and CRF on dopamine neurons: Emerging players in addiction. Brain research 59 19891960
1999 Actions of CRF and its analogs. Current medicinal chemistry 59 10519912
2011 Hypothalamic oxytocin attenuates CRF expression via GABA(A) receptors in rats. Brain research 58 21382355
2008 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. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 58 19078950
1998 Pyrazolo[1,5-a]pyrimidine CRF-1 receptor antagonists. Bioorganic & medicinal chemistry letters 57 9873487
1995 Behavioral, neurochemical, and immunological responses to CRF administration. Is CRF a mediator of stress? Annals of the New York Academy of Sciences 57 8597429
2010 Pre-clinical evidence that corticotropin-releasing factor (CRF) receptor antagonists are promising targets for pharmacological treatment of alcoholism. CNS & neurological disorders drug targets 56 20201818
2011 Urocortin 1 reduces food intake and ghrelin secretion via CRF(2) receptors. American journal of physiology. Endocrinology and metabolism 55 21540451
2010 Emerging role of alternative splicing of CRF1 receptor in CRF signaling. Acta biochimica Polonica 55 20234885
2017 Substance P and the Neurokinin-1 Receptor: The New CRF. International review of neurobiology 54 29056150
2007 The corticotropin-releasing factor (CRF) family of peptides as local modulators of adrenal function. Cellular and molecular life sciences : CMLS 53 17453142
2006 Regulation of synaptic transmission by CRF receptors. Reviews in the neurosciences 53 16878401
2006 Expression of corticotropin-releasing factor and CRF receptors in micturition pathways after cyclophosphamide-induced cystitis. American journal of physiology. Regulatory, integrative and comparative physiology 51 16614059
2013 Evolution and phylogeny of the corticotropin-releasing factor (CRF) family of peptides: expansion and specialization in the vertebrates. Journal of chemical neuroanatomy 50 24076419
2009 Functional differences between two CRF-related diuretic hormone receptors in Drosophila. The Journal of experimental biology 50 19749107
2007 Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal. Neuron 49 17296558
2002 Pharmacology and biology of corticotropin-releasing factor (CRF) receptors. Receptors & channels 49 12529934
2017 Contribution of amygdala CRF neurons to chronic pain. Experimental neurology 48 28830762
1999 Peripheral injection of a new corticotropin-releasing factor (CRF) antagonist, astressin, blocks peripheral CRF- and abdominal surgery-induced delayed gastric emptying in rats. The Journal of pharmacology and experimental therapeutics 48 10411571
2005 Listening to mutant mice: a spotlight on the role of CRF/CRF receptor systems in affective disorders. Neuroscience and biobehavioral reviews 47 15899517
1993 Amygdala kindling, anxiety, and corticotrophin releasing factor (CRF). Physiology & behavior 47 8415932
2003 Corticotropin-releasing factor (CRF) rapidly suppresses apoptosis by acting upstream of the activation of caspases. Journal of neurochemistry 46 12603831
1995 Down-regulation of PTH-PTHrP receptor of heart in CRF: role of [Ca2+]i. Kidney international 46 7783417
1996 Expression of ionotropic glutamate receptor subunit mRNAs by paraventricular corticotropin-releasing factor (CRF) neurons. Neuroscience letters 45 8907325
2008 Proximal colon distension induces Fos expression in oxytocin-, vasopressin-, CRF- and catecholamines-containing neurons in rat brain. Brain research 44 18955037
2012 Experimental neuropathy increases limbic forebrain CRF. European journal of pain (London, England) 40 21684787
2006 Corticotropin Releasing Factor (CRF) activation of NF-kappaB-directed transcription in leukocytes. Cellular and molecular neurobiology 39 16633893
1996 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. The Journal of clinical endocrinology and metabolism 38 8636316
2016 An Update on CRF Mechanisms Underlying Alcohol Use Disorders and Dependence. Frontiers in endocrinology 37 27818644
2010 VIP, CRF, and PACAP act at distinct receptors to elicit different cAMP/PKA dynamics in the neocortex. Cerebral cortex (New York, N.Y. : 1991) 37 20699230
2006 Involvement of the corticotropin-releasing factor (CRF) type 2 receptor in CRF-induced thyrotropin release by the amphibian pituitary gland. General and comparative endocrinology 37 17188689
2019 Prefrontal Corticotropin-Releasing Factor (CRF) Neurons Act Locally to Modulate Frontostriatal Cognition and Circuit Function. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 30651328
2002 GRK3 regulation during CRF- and urocortin-induced CRF1 receptor desensitization. Biochemical and biophysical research communications 35 12413940
1999 Characterisation using microphysiometry of CRF receptor pharmacology. European journal of pharmacology 35 10497910
1998 Corticotropin-releasing factor (CRF) agonists stimulate testosterone production in mouse leydig cells through CRF receptor-1. Endocrinology 34 9449637
2005 Peripherally administered CRF stimulates colonic motility via central CRF receptors and vagal pathways in conscious rats. American journal of physiology. Regulatory, integrative and comparative physiology 32 16284082
2018 Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking. Handbook of experimental pharmacology 31 29374836
2013 Intermittent access ethanol consumption dysregulates CRF function in the hypothalamus and is attenuated by the CRF-R1 antagonist, CP-376395. Addiction biology 31 23362976
2018 CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension. BMC cancer 30 29321030
2013 Corticotropin-releasing factor (CRF) and α 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats. The international journal of neuropsychopharmacology 30 23590881
2013 miR-449a contributes to glucocorticoid-induced CRF-R1 downregulation in the pituitary during stress. Molecular endocrinology (Baltimore, Md.) 30 23893957
2007 CRF1 not glucocorticoid receptors mediate prepulse inhibition deficits in mice overexpressing CRF. Biological psychiatry 30 17716630
1997 Regulation of corticotropin-releasing factor (CRF) messenger ribonucleic acid and CRF peptide in the amygdala: studies in primary amygdalar cultures. Endocrinology 30 9348205
2015 Endogenous CRF in rat large intestine mediates motor and secretory responses to stress. Neurogastroenterology and motility 28 26611915
2011 Members of CRF family and their receptors: from past to future. Current medicinal chemistry 27 21568890
2014 Grin1 receptor deletion within CRF neurons enhances fear memory. PloS one 26 25340785
2001 Electrophysiological effects of sustained delivery of CRF and its receptor agonists in hippocampal slices. Brain research 26 11730708
2016 C1ql1/Ctrp14 and C1ql4/Ctrp11 promote angiogenesis of endothelial cells through activation of ERK1/2 signal pathway. Molecular and cellular biochemistry 25 27734226
2011 Effects of citalopram on serotonin and CRF systems in the midbrain of primates with differences in stress sensitivity. Journal of chemical neuroanatomy 25 21683135
2008 Residues of corticotropin releasing factor-binding protein (CRF-BP) that selectively abrogate binding to CRF but not to urocortin 1. The Journal of biological chemistry 25 18234674