Affinage

CBLN1

Cerebellin-1 · UniProt P23435

Length
193 aa
Mass
21.1 kDa
Annotated
2026-04-28
38 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CBLN1 is a secreted glycoprotein of the C1q/TNF superfamily that functions as a bidirectional trans-synaptic organizer and axon guidance cue in the developing and mature nervous system. CBLN1 assembles into hexamers that bridge presynaptic neurexins (NRXN1β/NRXN2) to postsynaptic GluD2 (in cerebellum) or GluD1 (in amygdala and hypothalamus), and this tripartite complex is both necessary and sufficient to induce and maintain excitatory synapses, while simultaneously suppressing inhibitory synapse formation through a Src-family kinase pathway (PMID:20537373, PMID:20395510, PMID:18524896, PMID:24467251). CBLN1 is released from axonal lysosomes in an activity- and Ca²⁺-dependent manner, retained on axonal surfaces by neurexin, and accumulates at boutons via GluD2 binding; its expression is regulated transcriptionally by a lncRNA-PM/Pax6/Mll1-H3K4me3 axis and post-transcriptionally by YTHDF3-BTG2-mediated mRNA decay, while chronic neuronal activity represses Cbln1 via L-type Ca²⁺ channels and calcineurin (PMID:31072786, PMID:34111112, PMID:38205248, PMID:19403810). Beyond synaptogenesis, CBLN1 acts as an autocrine axon growth and attractive guidance cue through NRXN2 during early development and specifies distal corticospinal axon targeting (PMID:36395107, PMID:36823038).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 Medium

    Establishing that CBLN1 forms specific homomeric and heteromeric (with CBLN3) complexes answered the question of whether cerebellin-family members interact physically, suggesting they operate as oligomeric secreted signals.

    Evidence Yeast two-hybrid screen and mammalian co-expression binding assays in HEK cells

    PMID:10964938

    Open questions at the time
    • No functional assay for the heteromeric complex
    • Stoichiometry and quaternary structure not resolved
    • In vivo relevance of heteromer not tested
  2. 2005 High

    The generation of Cbln1-null mice revealed that CBLN1 is essential for synapse integrity, long-term depression, and proper climbing fiber innervation at parallel fiber–Purkinje cell synapses, establishing it as a key trans-neuronal signaling molecule whose loss phenocopies GluD2 deletion.

    Evidence Cbln1 knockout mouse with anatomical, electrophysiological, and behavioral phenotyping; genetic epistasis with GluD2-null mice

    PMID:16234806

    Open questions at the time
    • Molecular receptor for CBLN1 not yet identified
    • Mechanism of secretion unknown
    • Whether CBLN1 acts directly or through intermediate molecules unclear
  3. 2005 Medium

    Demonstrating that hexameric (uncleaved) CBLN1 is the secreted functional form, and that proteolytic processing yields trimers or destroys assembly, resolved how oligomeric state relates to biological activity.

    Evidence Yeast two-hybrid, mammalian expression, and proteolytic processing analysis of synaptic compartment fractions

    PMID:16135095

    Open questions at the time
    • No functional readout linking hexamer vs. trimer to synaptogenic activity
    • Protease identity and regulation unknown
  4. 2006 High

    Genetic epistasis between Cbln1 and Cbln3 knockouts revealed a 'hide-and-run' ER retention mechanism in which CBLN3 requires CBLN1 for secretion and CBLN3 reciprocally modulates CBLN1 levels, establishing how heteromeric complex formation controls secretion.

    Evidence Cbln1/Cbln3 double-knockout mice, mutagenesis, structural modeling, secretion assays

    PMID:17030622

    Open questions at the time
    • Physiological significance of CBLN1/3 heteromer vs. CBLN1 homomer at synapses not tested
    • ER retention receptor for CBLN3 not identified
  5. 2008 High

    Recombinant CBLN1 application to knockout cultures and in vivo fully restored functional synapses and rescued ataxia in adult mice, proving that CBLN1 is not only a developmental factor but continuously required for synapse maintenance.

    Evidence Recombinant CBLN1 application to knockout cultures and slices, in vivo cerebellar injection with electrophysiology and EM

    PMID:18524896

    Open questions at the time
    • Postsynaptic receptor still not identified at this point
    • Turnover kinetics and half-life of CBLN1 at synapses unknown
  6. 2009 High

    Multiple studies converged to define CBLN1's synaptic localization and regulation: ultrastructural immunogold localized CBLN1 to the synaptic cleft, binding assays showed hexamer-specific binding to postsynaptic densities, trans-neuronal trafficking to Purkinje cells was demonstrated, and activity-dependent repression of Cbln1 via L-type Ca²⁺/calcineurin was established.

    Evidence Postembedding immunogold EM, recombinant fragment binding in weaver/pcd mutant cerebella, trans-neuronal trafficking in GluD2-null mice, chronic depolarization with pharmacological dissection

    PMID:19200061 PMID:19250438 PMID:19344768 PMID:19403810

    Open questions at the time
    • Identity of postsynaptic binding partner still formally unresolved
    • Calcineurin targets at the Cbln1 promoter not identified
    • Mechanism of trans-neuronal uptake unknown
  7. 2010 High

    Two simultaneous landmark studies identified GluD2 as the postsynaptic receptor and neurexins as the presynaptic receptor for CBLN1, establishing the tripartite NRXN–CBLN1–GluD2 complex as the minimal trans-synaptic unit for synapse induction.

    Evidence Co-immunoprecipitation, Cbln1-coated bead reconstitution, NRXN knockdown, in vivo competitive inhibition, direct pull-down of CBLN1-GluD2

    PMID:20395510 PMID:20537373

    Open questions at the time
    • Structural basis of the tripartite complex not determined
    • Whether CBLN1 binds other postsynaptic receptors besides GluD2 unknown
    • Signaling downstream of GluD2 engagement uncharacterized
  8. 2012 High

    Time-lapse imaging revealed that NRXN–CBLN1–GluD2 signaling drives dynamic presynaptic structural remodeling (protrusions that encapsulate spines), establishing the morphogenetic mechanism by which this complex builds synapses.

    Evidence Time-lapse imaging in organotypic cerebellar culture, ultrastructural analysis, GluD2/Nrxn knockout analysis

    PMID:23141067

    Open questions at the time
    • Cytoskeletal effectors downstream of neurexin engagement not identified
    • Whether this protrusion mechanism operates outside cerebellum unknown
  9. 2014 High

    Discovery that CBLN1–GluD2 signaling actively suppresses inhibitory synapse formation via Src-family kinases expanded CBLN1's role from excitatory synaptogenesis to bidirectional synapse-type control.

    Evidence Electrophysiology and immunohistochemistry in cbln1-null and Cbln1/GluD2 double-null cerebellar slices, Src-family kinase inhibitor pharmacology

    PMID:24467251

    Open questions at the time
    • Direct Src substrate linking GluD2 signaling to inhibitory synapse suppression unknown
    • Whether this extends beyond Purkinje cells untested
  10. 2017 High

    Crystal structures of CBLN1 and CBLN4 C1q domains and EM reconstruction of hexameric CBLN1 revealed the structural basis for receptor selectivity: loop CD divergence explains differential GluD2 binding, while NRXN1β contacts strand β10 of the splice insert.

    Evidence X-ray crystallography (2.2 Å), negative-stain EM (13 Å), binding assays

    PMID:28877468

    Open questions at the time
    • No co-crystal of the full tripartite complex
    • How hexamer-to-trimer transition affects receptor engagement structurally unresolved
  11. 2017 High

    UBE3A was identified as a transcriptional repressor of Cbln1 in VTA glutamatergic neurons, and viral restoration of CBLN1 rescued sociability deficits, linking CBLN1 to autism-related circuitry via the UBE3A pathway.

    Evidence In vivo UBE3A overexpression, Cbln1 conditional deletion in VTA, viral Cbln1 restoration, electrophysiology

    PMID:28297715

    Open questions at the time
    • Mechanism by which UBE3A represses Cbln1 transcription not defined
    • Whether postsynaptic GluD1 or GluD2 mediates VTA synapse effects not resolved
  12. 2019 High

    Live imaging demonstrated that CBLN1 is released from axonal lysosomes (not conventional secretory vesicles) in an activity- and Ca²⁺-dependent, tetanus toxin-insensitive manner, redefining its secretion mechanism as lysosomal exocytosis.

    Evidence Cbln1-pHluorin live imaging, tetanus neurotoxin insensitivity, cathepsin B co-release, lysosome disruption, Neu1 overexpression in vivo

    PMID:31072786

    Open questions at the time
    • Ca²⁺ sensor for lysosomal CBLN1 exocytosis not identified
    • Whether lysosomal release mechanism generalizes to other C1q-family members unknown
  13. 2020 High

    Sparse knockout studies showed that CBLN1/GluD2-dependent competitive synaptogenesis between neighboring Purkinje cells shapes dendritic territory, expanding CBLN1's role from synapse formation to dendrite morphogenesis.

    Evidence MADM-based sparse and global GluD2 knockout, developmental analyses, CBLN1/GluD2 overexpression, genetic epistasis

    PMID:33352118

    Open questions at the time
    • Molecular mechanism coupling synaptogenesis to dendrite elaboration not resolved
    • Whether competitive mechanism operates in other brain regions unknown
  14. 2021 Medium

    Identification of lncRNA-PM as a recruiter of Pax6 and Mll1 to the Cbln1 promoter to deposit H3K4me3 established the first epigenetic transcriptional activation mechanism for Cbln1.

    Evidence ChIP for H3K4me3/Pax6/Mll1 at Cbln1 locus, lncRNA-PM knockdown with synaptic and behavioral phenotyping

    PMID:34111112

    Open questions at the time
    • Developmental timing and cell-type specificity of lncRNA-PM regulation not fully characterized
    • Whether other lncRNAs regulate Cbln1 unknown
  15. 2022 Medium

    CBLN1 was shown to function as an axon growth and guidance cue during early development, acting through NRXN2 rather than through its synaptogenic receptor context, revealing a pre-synaptogenic role for CBLN1.

    Evidence Mouse and chick embryo conditional knockouts and gain-of-function, receptor identification (Nrxn2), axon tracing

    PMID:36395107

    Open questions at the time
    • Signaling pathway downstream of NRXN2 for axon guidance not identified
    • Whether guidance and synaptogenic functions are temporally separable in the same neuron unknown
  16. 2023 Medium

    CBLN1 was shown to direct distal corticospinal axon targeting: misexpression redirected cervical-projecting axons past their normal targets toward thoracic segments, extending the guidance function to cortical motor circuitry.

    Evidence In utero electroporation and AAV-mediated misexpression of CBLN1 in corticospinal neurons, in vivo axon tracing

    PMID:36823038

    Open questions at the time
    • Receptor mediating corticospinal targeting not identified
    • Whether CBLN1 acts cell-autonomously or as a secreted gradient cue in this context unclear
  17. 2025 Medium

    D-serine was identified as a competitive inhibitor of the CBLN1–GluD1 interaction, establishing a modulatory mechanism for CBLN1 signaling outside the cerebellum in amygdala circuits relevant to pain processing.

    Evidence In vitro cell-binding concentration-response assay, ex vivo electrophysiology in central amygdala slices, in vivo intra-CeA injection and behavioral testing

    PMID:39890638

    Open questions at the time
    • Whether D-serine modulates CBLN1–GluD2 interaction similarly untested
    • Structural basis of competitive inhibition unknown
    • Physiological D-serine concentrations at these synapses not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of the complete NRXN–CBLN1–GluD tripartite complex, the intracellular signaling cascades downstream of GluD2/GluD1 engagement by CBLN1, the Ca²⁺ sensor mediating lysosomal CBLN1 exocytosis, and whether CBLN1's axon guidance and synaptogenic functions are mediated by distinct downstream pathways or converge on shared effectors.
  • No co-crystal structure of the ternary NRXN–CBLN1–GluD complex
  • Intracellular signaling downstream of GluD engagement by CBLN1 largely uncharacterized
  • Ca²⁺ sensor for lysosomal exocytosis not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0005198 structural molecule activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 4 GO:0005764 lysosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 9 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-9609507 Protein localization 2
Partners
CBLN2CBLN3GRID1GRID2NRXN1NRXN2UBE3A
Complex memberships
CBLN1 homohexamerCBLN1-CBLN3 heteromeric complexNRXN-CBLN1-GluD2 tripartite complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Cbln1 forms a tripartite trans-synaptic complex by binding to the N-terminal domain (NTD) of postsynaptic GluRdelta2 (GluD2) and to presynaptic neurexins (NRXNs), bridging pre- and postsynaptic elements at cerebellar parallel fiber-Purkinje cell synapses. The synaptogenic activity of GluRdelta2 is abolished in Cbln1-null mice and restored by recombinant Cbln1; knockdown of NRXNs or competitive application of GluRdelta2-NTD or NRXN1β extracellular domain also suppresses Cbln1 synaptogenic activity. Co-immunoprecipitation, cerebellar primary cultures from Cbln1-knockout mice, recombinant protein rescue, NRXN knockdown, in vivo competitive inhibition experiments Cell High 20537373
2010 Cbln1 is a direct ligand for the orphan postsynaptic receptor GluD2; GluD2 expression combined with exogenously applied Cbln1 is necessary and sufficient to induce new synapses in vitro and in the adult cerebellum in vivo. Cbln1-coated beads directly induce presynaptic differentiation and indirectly cluster postsynaptic molecules via GluD2, demonstrating bidirectional synapse-organizing activity. Direct binding assay (Cbln1-GluD2 pull-down), bead-coating reconstitution assay, in vitro synapse induction, in vivo injection in adult mice Science High 20395510
2005 Cbln1 is a glycoprotein secreted from cerebellar granule cells that is essential for matching and maintenance of pre- and postsynaptic elements at parallel fiber-Purkinje cell synapses, proper climbing fiber innervation patterns, and induction of long-term depression at parallel fiber-Purkinje cell synapses. Cbln1-null mice phenocopy GluRdelta2-null mice, placing Cbln1 in the same transneuronal signaling pathway. cbln1 knockout mouse phenotype analysis (anatomical, electrophysiological, behavioral), genetic epistasis with GluRdelta2-null mice, secretion assay Nature neuroscience High 16234806
2008 Recombinant Cbln1 specifically and reversibly induces parallel fiber synapse formation in dissociated cbln1-null Purkinje cells in culture and in acutely prepared cbln1-null cerebellar slices, creating electrophysiologically functional and ultrastructurally normal synapses. A single injection of recombinant Cbln1 rescues ataxia in adult cbln1-null mice in vivo by completely restoring parallel fiber synapses, demonstrating that Cbln1 is required for both development and maintenance of these synapses. Recombinant Cbln1 application to knockout cultures and slices, in vivo cerebellar injection, electrophysiology, electron microscopy The Journal of neuroscience High 18524896
2000 Cbln1 forms homomeric complexes and binds specifically to Cbln3 to form heteromeric complexes; Cbln3 cannot form homomers on its own. These interactions are specific, as C1qB binds neither Cbln1 nor Cbln3. Both proteins are co-expressed in cerebellar and dorsal cochlear nucleus granule neurons, suggesting they function as a secreted heteromeric complex in vivo. Yeast two-hybrid screen, mammalian co-expression binding assays The Journal of neuroscience Medium 10964938
2005 Only uncleaved Cbln1 (containing the cerebellin motif) is released and assembles into hexameric complexes. Cleavage at the N-terminus of the cerebellin sequence yields trimeric complexes by separating the trimer-mediating C1q domain from N-terminal cysteines that mediate higher-order oligomerization. Cleavage at the C-terminus of the cerebellin motif disrupts the C1q domain and abolishes all subunit interactions. Yeast two-hybrid, mammalian expression systems, proteolytic processing analysis of synaptic compartment fractions Journal of neurochemistry Medium 16135095
2006 Cbln1 is secreted from cerebellar granule cells in complex with Cbln3. Cbln1 and Cbln3 reciprocally regulate each other's degradation and secretion: Cbln1-null mice lack both proteins, while Cbln3-null mice lack Cbln3 but have ~6-fold increased Cbln1. Cbln3 cannot form homomers and is secreted only when bound to Cbln1. A single arginine in Cbln3 creates a steric clash that is masked upon Cbln1 binding ('hide-and-run' ER retention mechanism), conferring Cbln3's unique secretion dependence. Cbln1/Cbln3 double-knockout mouse analysis, structural modeling, mutation analysis, secretion assays in transfected cells Molecular and cellular biology High 17030622
2007 Cbln1 is localized to the endolysosomal compartment of neurons, as demonstrated by colocalization with cathepsin D but not with ER or Golgi markers. This endolysosomal localization represents the mechanism for regulated degradation of Cbln1 in vivo. In Cbln3-null mice, Cbln1 levels are dramatically increased in the cerebellum but unchanged in extracerebellar neurons. Immunohistochemistry with organelle markers, cbln1-lacZ transgenic mice, fractionation The European journal of neuroscience Medium 18001291
2009 Cbln1 released from granule cells undergoes anterograde trans-neuronal transport to Purkinje cells and Bergmann glia, entering the endolysosomal trafficking system. Cbln1 is absent from Purkinje cells and Bergmann glia in GluRdelta2-null mice, indicating mechanistic convergence on Cbln1 trafficking. Ectopic postsynaptic expression of Cbln1 in Purkinje cells of L7-cbln1 transgenic mice ameliorates locomotor deficits of cbln1-null mice. Trans-neuronal trafficking assay, GluRdelta2-null mouse analysis, L7-cbln1 transgenic mouse rescue, immunohistochemistry Molecular and cellular neurosciences Medium 19344768
2009 Recombinant hexameric Cbln1 (but not trimeric or N-terminal/C-terminal fragments) specifically binds to postsynaptic sites of parallel fiber-Purkinje cell synapses in a saturable and replaceable manner. Binding is present in weaver cerebellum (lacking granule cells) but absent in pcd cerebellum (lacking Purkinje cells), localizing the binding site to postsynaptic densities. Subcellular fractionation confirms Cbln1 binds to synaptosomal and postsynaptic density fractions. Recombinant Cbln1 binding assay in primary cultures and acute slices, weaver and pcd mutant mouse cerebellum, subcellular fractionation The European journal of neuroscience High 19200061
2009 Cbln1 accumulates in the synaptic cleft of parallel fiber-Purkinje cell synapses as revealed by postembedding immunogold electron microscopy with antigen-exposing methods. Cbln1 co-localizes with Cbln3 and GluRdelta2 specifically at these synapses (not at other Purkinje cell synapses), providing anatomical basis for a common signaling pathway. Light microscopy with pepsin pretreatment, postembedding immunogold electron microscopy The European journal of neuroscience High 19250438
2009 Chronic neuronal activity represses cbln1 mRNA expression in mature granule cells via L-type voltage-dependent Ca2+ channels and calcineurin signaling. This activity-dependent downregulation of Cbln1 protein reduces the number of excitatory synapses on Purkinje cell dendrites, and adding exogenous Cbln1 prevents this synapse reduction. Immature granule cell depolarization prevents cbln1 mRNA induction, suggesting a developmental switch mechanism. Chronic K+/kainate stimulation of granule cell cultures, pharmacological blockade (L-type Ca2+ channel blockers, calcineurin inhibitors), exogenous Cbln1 rescue, synapse counting The Journal of neuroscience High 19403810
2012 Cbln1 released from parallel fibers induces dynamic structural changes (protrusions and circular encapsulation structures) in presynaptic parallel fiber axons via a mechanism requiring postsynaptic GluD2 and presynaptic neurexin (Nrxn). Time-lapse imaging shows Nrxn-Cbln1-GluD2 signaling induces PF protrusions that encapsulate Purkinje cell spines, leading to accumulation of synaptic vesicles and GluD2, thereby forming mature synapses via positive feedback. Time-lapse imaging in organotypic culture, ultrastructural analysis in vivo, GluD2/Nrxn knockout analysis Neuron High 23141067
2012 Cbln1 and Cbln2 have similar binding activities to β-neurexins and GluD2 (Grid2). Targeted ectopic expression of Cbln2 in Purkinje cells rescues cerebellar deficits in Cbln1-null mice, demonstrating functional redundancy through shared receptor-binding properties. However, Cbln2 does not substitute for Cbln1 in thalamic neurons affecting striatal synapses, indicating region-specific divergence. Binding assays, transgenic rescue (Cbln2 expressed in Cbln1-null background), Cbln2-knockout mouse generation and analysis Journal of neurochemistry Medium 22117778
2017 Crystal structures of the homotrimeric C1q domains of Cbln1 and Cbln4 at 2.2 Å and 2.3 Å resolution reveal that structural and sequence divergence in loop CD underlies the difference between Cbln1 and Cbln4 in GluD2 binding. Negative-stain electron microscopy reconstruction of hexameric full-length Cbln1 at 13 Å resolution shows Nrxn1β binds to the N-terminal region of Cbln4 via strand β10 of the S4 insert. X-ray crystallography, negative-stain electron microscopy reconstruction, binding assays Cell reports High 28877468
2019 Cbln1 is released from lysosomes in axons (but not dendrites) of cerebellar granule cells in an activity- and Ca2+-dependent manner. Exocytosed Cbln1 is retained on axonal surfaces by binding to presynaptic neurexin, then diffuses laterally and accumulates at boutons by binding postsynaptic GluD2. Cbln1 exocytosis is insensitive to tetanus neurotoxin, accompanied by cathepsin B release, and inhibited by lysosome disruption. Overexpression of lysosomal sialidase Neu1 inhibits Cbln1/cathepsin B exocytosis and reduces axonal bouton formation in vivo. Live imaging of Cbln1-pHluorin, tetanus neurotoxin treatment, Ca2+ manipulation, lysosome disruption, Neu1 overexpression in vitro and in vivo Neuron High 31072786
2017 UBE3A (a ubiquitin ligase with nuclear transcriptional co-regulatory function) downregulates Cbln1 expression in VTA glutamatergic neurons. Cbln1 deletion in VTA impairs sociability and weakens glutamatergic transmission. Viral restoration of Cbln1 in VTA glutamatergic neurons reverses sociability deficits caused by Ube3a overexpression and/or seizures. In vivo mouse genetics (UBE3A overexpression, Cbln1 conditional deletion), chemogenetic activation, viral vector-based Cbln1 restoration, whole-cell electrophysiology Nature High 28297715
2010 The flap loop (Arg321-Trp339) in the N-terminal domain of GluD2 is a crucial region for binding to Cbln1 and for induction of presynaptic differentiation. Single amino acid substitutions of either Arg321 or Trp323 to alanine are sufficient to abolish both Cbln1 binding and presynaptic differentiation induction. Site-directed mutagenesis of GluD2, HEK cell expression, binding assay, presynaptic differentiation assay, homology modeling Biochemical and biophysical research communications Medium 20599760
2014 Cbln1-GluD2 signaling downregulates the formation and function of inhibitory synapses between Purkinje cells and interneurons. Recombinant Cbln1 reverses increased inhibitory synapse density and miniature IPSC amplitude in cbln1-null slices, but has no effect in Cbln1/GluD2 double-null mice. The effect on inhibitory transmission is mediated through a tyrosine kinase (Src-family kinase) pathway, as Src inhibition suppresses the increased inhibitory currents in cbln1-null Purkinje cells. Immunohistochemistry (VGAT antibody), whole-cell patch-clamp in cerebellar slices, recombinant Cbln1 application, Src-family kinase inhibitor pharmacology, double-knockout analysis The European journal of neuroscience High 24467251
2020 Sparse but not global knockout of GluD2 causes under-elaboration of Purkinje cell dendrites in the deep molecular layer and overelaboration in the superficial layer, due to a deficit in Cbln1/GluD2-dependent competitive interactions during synaptogenesis. Genetic epistasis and overexpression analyses confirm Cbln1 drives these dendrite morphogenesis effects through competitive synaptogenesis. Sparse and global GluD2 knockout (MADM system), developmental analyses, Cbln1/GluD2 overexpression, genetic epistasis, computational modeling Neuron High 33352118
2022 Cbln1 functions as an axon growth and guidance cue during early neural development, acting in an autocrine manner from axons/growth cones of commissural neurons to promote axon growth, and as an attractive guidance cue from intermediate target tissues. These functions are mediated by neurexin-2 (Nrxn2) as the Cbln1 receptor for axon growth and guidance, distinct from its synaptogenic receptor context. Cbln1 also regulates cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Mouse and chick embryo experiments, loss-of-function (conditional knockout), gain-of-function, receptor identification (Nrxn2), axon tracing PLoS biology Medium 36395107
2023 Cbln1 expressed in corticospinal neurons (CSN) of medial sensorimotor cortex directs thoraco-lumbar axon extension. Cbln1 shows highest expression during peak axon extension toward thoraco-lumbar segments. Misexpression of Cbln1 in bulbar-cervical projecting CSN (via in utero electroporation or AAV) redirects these axons past normal targets toward thoracic segments, demonstrating sufficiency for specifying distal axon targeting. In utero electroporation, AAV-mediated gene delivery, in vivo axon tracing, gain-of-function The Journal of neuroscience Medium 36823038
2021 lncRNA-PM (lncRNA-Promoting Methylation) activates Cbln1 transcription through recruiting Pax6 and Mll1 to promote H3K4me3 at the Cbln1 regulatory region. Knockdown of lncRNA-PM reduces Cbln1 expression, impairs cerebellar synaptic integrity, and causes motor deficits. ChIP for H3K4me3 and Pax6/Mll1 at Cbln1 locus, lncRNA-PM knockdown in cerebellum, mRNA/protein measurement, synaptic morphology and behavioral analysis PLoS biology Medium 34111112
2023 YTHDF3 interacts with BTG2 and is involved in the decay of Cbln1 mRNA in the hippocampus, leading to downregulation of Cbln1 expression and abnormal synaptic function. Co-immunoprecipitation of YTHDF3-BTG2, mRNA decay assay, Cbln1 protein/mRNA measurement, synaptic functional analysis iScience Medium 38205248
2025 D-serine inhibits the interaction between Cbln1 and GluD1 in a concentration-dependent manner (IC50 ~300 µM) in an in vitro cell-binding assay. In ex vivo central amygdala slices, recombinant Cbln1 increases excitatory neurotransmission via GluD1, and this effect is partially blocked by D-serine pre-treatment. Intra-CeA rCbln1 injection modulates nocifensive responses and this is blocked by D-serine. In vitro cell-binding assay (concentration-response), ex vivo electrophysiology in central amygdala slices, in vivo intra-CeA injection and behavioral testing Cellular and molecular life sciences Medium 39890638
2023 In the VMHvl-arcuate circuit, VMHvl neurons form excitatory synapses onto AgRP/NPY arcuate neurons through a NRXN1-Cbln1-GluD1 transsynaptic complex. Increased UBE3A decreases Cbln1 gene expression in VMHvl, impairing this synapse and elevating aggression. Deletion of GluD1 in arcuate AgRP neurons reduces excitatory synapses from VMHvl and increases aggression. Targeted Ube3a deletion in VMHvl, GluD1 conditional knockout in AgRP neurons, chemogenetic/optogenetic circuit manipulations, electrophysiology bioRxivpreprint Medium 36909588

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell 402 20537373
2010 Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science (New York, N.Y.) 288 20395510
2005 Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nature neuroscience 267 16234806
2017 Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1. Nature 121 28297715
2008 Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 87 18524896
2000 Cbln3, a novel member of the precerebellin family that binds specifically to Cbln1. The Journal of neuroscience : the official journal of the Society for Neuroscience 68 10964938
2005 The structure and proteolytic processing of Cbln1 complexes. Journal of neurochemistry 62 16135095
2011 Cbln1 and its family proteins in synapse formation and maintenance. Current opinion in neurobiology 55 21342763
2016 Roles of Cbln1 in Non-Motor Functions of Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 27852787
2006 Cbln1 is essential for interaction-dependent secretion of Cbln3. Molecular and cellular biology 49 17030622
2012 Presynaptically released Cbln1 induces dynamic axonal structural changes by interacting with GluD2 during cerebellar synapse formation. Neuron 47 23141067
2019 Activity-Dependent Secretion of Synaptic Organizer Cbln1 from Lysosomes in Granule Cell Axons. Neuron 44 31072786
2020 GluD2- and Cbln1-mediated competitive interactions shape the dendritic arbors of cerebellar Purkinje cells. Neuron 37 33352118
2008 New (but old) molecules regulating synapse integrity and plasticity: Cbln1 and the delta2 glutamate receptor. Neuroscience 37 19124061
2009 Cbln1 accumulates and colocalizes with Cbln3 and GluRdelta2 at parallel fiber-Purkinje cell synapses in the mouse cerebellum. The European journal of neuroscience 31 19250438
2009 Activity-dependent repression of Cbln1 expression: mechanism for developmental and homeostatic regulation of synapses in the cerebellum. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 19403810
2007 Mapping of Cbln1-like immunoreactivity in adult and developing mouse brain and its localization to the endolysosomal compartment of neurons. The European journal of neuroscience 31 18001291
2012 Comparison of Cbln1 and Cbln2 functions using transgenic and knockout mice. Journal of neurochemistry 29 22117778
2013 Reevaluation of the role of parallel fiber synapses in delay eyeblink conditioning in mice using Cbln1 as a tool. Frontiers in neural circuits 21 24298240
2017 Cbln1 and Cbln4 Are Structurally Similar but Differ in GluD2 Binding Interactions. Cell reports 17 28877468
2012 Cbln1 and the δ2 glutamate receptor--an orphan ligand and an orphan receptor find their partners. Cerebellum (London, England) 16 20535596
2021 Long noncoding RNA PM maintains cerebellar synaptic integrity and Cbln1 activation via Pax6/Mll1-mediated H3K4me3. PLoS biology 14 34111112
2014 The role of Cbln1 on Purkinje cell synapse formation. Neuroscience research 14 24607546
2022 Cbln1 regulates axon growth and guidance in multiple neural regions. PLoS biology 13 36395107
2014 Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells. The European journal of neuroscience 13 24467251
2009 Characterization of trans-neuronal trafficking of Cbln1. Molecular and cellular neurosciences 12 19344768
2009 Cbln1 binds to specific postsynaptic sites at parallel fiber-Purkinje cell synapses in the cerebellum. The European journal of neuroscience 11 19200061
2023 Cbln1 Directs Axon Targeting by Corticospinal Neurons Specifically toward Thoraco-Lumbar Spinal Cord. The Journal of neuroscience : the official journal of the Society for Neuroscience 10 36823038
2018 Improvement of cerebellar ataxic gait by injecting Cbln1 into the cerebellum of cbln1-null mice. Scientific reports 9 29670152
2025 D-Serine disrupts Cbln1 and GluD1 interaction and affects Cbln1-dependent synaptic effects and nocifensive responses in the central amygdala. Cellular and molecular life sciences : CMLS 7 39890638
2018 Evidence for generative homology of cerebellum and cerebellum-like structures in an elasmobranch fish based on Pax6, Cbln1 and Grid2 expression. The Journal of comparative neurology 7 29888788
2010 Flap loop of GluD2 binds to Cbln1 and induces presynaptic differentiation. Biochemical and biophysical research communications 7 20599760
2023 YTHDF3 modulates the Cbln1 level by recruiting BTG2 and is implicated in the impaired cognition of prenatal hypoxia offspring. iScience 6 38205248
2025 Trans-synaptic signaling through GRID1/glutamate receptor delta-1 and CBLN1/cerebellin-1 facilitates autophagic flux in central amygdala and prevents chronic pain. Autophagy 4 41147487
2016 Developmental Hypothyroxinemia and Hypothyroidism Reduce Parallel Fiber-Purkinje Cell Synapses in Rat Offspring by Downregulation of Neurexin1/Cbln1/GluD2 Tripartite Complex. Biological trace element research 4 27033232
2021 Family-Based Cohort Association Study of PRKCB1, CBLN1 and KCNMB4 Gene Polymorphisms and Autism in Polish Population. Journal of autism and developmental disorders 3 34562210
2023 UBE3A and transsynaptic complex NRXN1-CBLN1-GluD1 in a hypothalamic VMHvl-arcuate feedback circuit regulates aggression. bioRxiv : the preprint server for biology 2 36909588
2026 CBLN1 inhibits the inflammatory response by targeting GluD1 thereby alleviating resiniferatoxin-induced postherpetic neuralgia in mice. Journal of neuropathology and experimental neurology 0 41144370