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HGNC Approved Gene Symbol: CBLN1
Cytogenetic location: 16q12.1 Genomic coordinates (GRCh38): 16:49,277,917-49,281,838 (from NCBI)
Precerebellin, or CBLN1, is the precursor of a conserved brain-specific hexadecapeptide termed cerebellin. CBLN1 and other members of the precerebellin family also contain a C-terminal C1q signature domain (see 120550) that mediates trimeric assembly of atypical collagen complexes. However, precerebellins do not contain a collagen motif, suggesting that they are not conventional components of the extracellular matrix (Pang et al., 2000).
Using an oligonucleotide complementary to cerebellin to screen a human cerebellum cDNA library, Urade et al. (1991) cloned CBLN1. The deduced 193-amino acid protein contains a hydrophobic N terminus followed by the cerebellin sequence. It also contains 3 potential N-glycosylation sites. Over about 145 amino acids in its C terminus, CBLN1 shares 31.3% identity with C1QB (120570), but it lacks N-terminal collagen-like motifs. The cerebellin peptide is flanked by val-arg and glu-pro residues, suggesting that it is not liberated from precerebellin by the classical dibasic amino acid proteolytic mechanism seen in many neuropeptide precursors. Northern blot analysis of human cerebellum detected transcripts of 2.3, 2.8, and 3.0 kb, and similar transcripts were detected in mouse and rat cerebellum. Precerebellin expression was low in embryonic rat and increased significantly after birth.
Kavety et al. (1994) cloned the murine homolog of Cbln1, and a closely related gene, Cbln2 (600433). The predicted amino acid sequence of Cbln2 is 88% identical to the C-terminal region of Cbln1.
Using Northern blot analysis, Pang et al. (2000) found several Cbln1 transcripts expressed in adult mouse cerebellum. Low levels of expression were detected in forebrain and spinal cord, but not in other adult mouse tissue examined. Examination of brain samples from embryonic and young mice revealed weak Cbln1 expression in whole brain beginning at embryonic day 15.5. Expression began to increase to adult levels in cerebellum beginning at postnatal day 3.
Kavety et al. (1994) noted that the mouse 'staggerer' mutant (see 600825) appears to lack cerebellin completely.
Using a yeast 2-hybrid assay, Pang et al. (2000) found that mouse Cbln1 and Cbln3 (612978) interacted. Cbln1 could also interact with itself.
Iijima et al. (2007) showed that mouse Cbln1, Cbln2, and Cbln4 (615029) were secreted into the culture medium of transfected cells, whereas Cbln3 was retained within the endoplasmic reticulum (ER) or cis Golgi. Protein interaction assays showed that all Cbln proteins could form homomeric complexes. They also assembled into heteromeric complexes upon coexpression, but not when mixed following secretion. Coexpression of Cbln1 with Cbln3 reciprocally permitted a portion of Cbln3 to be secreted and a portion of Cbln1 to be retained in the ER/Golgi.
Matsuda et al. (2010) found that Cbln1 binds directly to the N-terminal domain of the glutamate receptor delta-2 (Grid2; 602368). Grid2 expression by postsynaptic cells, combined with exogenously applied Cbln1, was necessary and sufficient to induce new synapses in vitro and in the adult mouse cerebellum in vivo. Further, beads coated with recombinant Cbln1 directly induced presynaptic differentiation and indirectly caused clustering of postsynaptic molecules via Grid2. Matsuda et al. (2010) concluded that the Cbln1-Grid2 complex is a unique synapse organizer that acts bidirectionally on both pre- and postsynaptic components in the cerebellum.
Using in vitro binding and Western blot analysis, Wei et al. (2012) found that mouse Cbln1, Cbln2, and Cbln4 had unique binding partners and/or binding affinities, suggesting that they function in multiple signaling pathways. Cbln1 bound consistently to the glutamate receptors Grid1 (610659) and Grid2, whereas Cbln2 bound more weakly to Grid1 and Grid2. Both Cbln1 and Cbln2 bound to specific isoforms of the neurexins Nrxn1 (600565), Nrxn2 (600566), and Nrxn3 (600567). In contrast, Cbln4 bound robustly to the netrin receptor Dcc (120470) and competed with netrin (NTN1; 601614) for Dcc binding.
Using in vivo mouse genetics, Krishnan et al. (2017) showed that increasing UBE3A (601623) in the nucleus downregulated the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repressed Cbln1 and exposed sociability impairments in mice with asymptomatic increases in UBE3A. This Ube3a-seizure synergy mapped to glutamate neurons of the midbrain ventral tegmental area (VTA), where Cbln1 deletions impaired sociability and weakened glutamatergic transmission. Krishnan et al. (2017) provided preclinical evidence that viral vector-based chemogenetic activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. Krishnan et al. (2017) concluded that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the protein interaction network of autism genes.
Hartz (2009) mapped the CBLN1 gene to chromosome 16q12.1 based on an alignment of the CBLN1 sequence (GenBank M58583) with the genomic sequence (GRCh37).
Kavety et al. (1994) mapped the mouse Cbln1 gene to the central region of chromosome 8, 2.3 cM distal of Junb (165161) and 6.0 cM proximal of Mt1 (see 156350). JUNB maps to human chromosome 19p13.2, and MT1 maps to human chromosome 16q13.
Hartz, P. A. Personal Communication. Baltimore, Md. 8/26/2009.
Iijima, T., Miura, E., Matsuda, K., Kamekawa, Y., Watanabe, M., Yuzaki, M. Characterization of a transneuronal cytokine family Cbln: regulation of secretion by heteromeric assembly. Europ. J. Neurosci. 25: 1049-1057, 2007. [PubMed: 17331201] [Full Text: https://doi.org/10.1111/j.1460-9568.2007.05361.x]
Kavety, B., Jenkins, N. A., Fletcher, C. F., Copeland, N. G., Morgan, J. I. Genomic structure and mapping of precerebellin and a precerebellin-related gene. Brain Res. Molec. Brain Res. 27: 152-156, 1994. [PubMed: 7877445] [Full Text: https://doi.org/10.1016/0169-328x(94)90196-1]
Krishnan, V., Stoppel, D. C., Nong, Y., Johnson, M. A., Nadler, M. J. S., Ozkaynak, E., Teng, B. L., Nagakura, I., Mohammad, F., Silva, M. A., Peterson, S., Cruz, T. J., Kasper, E. M., Arnaout, R., Anderson, M. P. Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1. Nature 543: 507-512, 2017. [PubMed: 28297715] [Full Text: https://doi.org/10.1038/nature21678]
Matsuda, K., Miura, E., Miyazaki, T., Kakegawa, W., Emi, K., Narumi, S., Fukazawa, Y., Ito-Ishida, A., Kondo, T., Shigemoto, R., Watanabe, M., Yuzaki, M. Cbln1 is a ligand for an orphan glutamate receptor delta-2, a bidirectional synapse organizer. Science 328: 363-368, 2010. [PubMed: 20395510] [Full Text: https://doi.org/10.1126/science.1185152]
Pang, Z., Zuo, J., Morgan, J. I. Cbln3, a novel member of the precerebellin family that binds specifically to Cbln1. J. Neurosci. 20: 6333-6339, 2000. [PubMed: 10964938] [Full Text: https://doi.org/10.1523/JNEUROSCI.20-17-06333.2000]
Urade, Y., Oberdick, J., Molinar-Rode, R., Morgan, J. I. Precerebellin is a cerebellum-specific protein with similarity to the globular domain of complement C1q B chain. Proc. Nat. Acad. Sci. 88: 1069-1073, 1991. [PubMed: 1704129] [Full Text: https://doi.org/10.1073/pnas.88.3.1069]
Wei, P., Pattarini, R., Rong, Y., Guo, H., Bansal, P. K., Kusnoor, S. V., Deutch, A. Y., Parris, J., Morgan, J. I. The Cbln family of proteins interact with multiple signaling pathways. J. Neurochem. 121: 717-729, 2012. [PubMed: 22220752] [Full Text: https://doi.org/10.1111/j.1471-4159.2012.07648.x]