Alternative titles; symbols
HGNC Approved Gene Symbol: SEMA4C
Cytogenetic location: 2q11.2 Genomic coordinates (GRCh38) : 2:96,859,718-96,870,830 (from NCBI)
Neural networks that are complicated but specific to each neuron are formed during development when growth cones make specific pathway choices and find their correct targets using a variety of guidance molecules in their surroundings. Semaphorins (SEMAs), such as SEMA4C, are transmembrane and secreted proteins that appear to function during growth cone guidance. These proteins contain a conserved sema domain of approximately 500 amino acids (summary by Inagaki et al., 1995).
Inagaki et al. (1995) cloned a novel mouse semaphorin gene, Sema4c, which they named SemaF. In situ hybridization detected SemaF expression throughout brain and spinal cord of E15.5, E16.5, and P1 mice. In the central nervous system, expression was very high in the primordia of the neocortex, hippocampus, thalamus, hypothalamus, tectum, pontine nuclei, spinal cord, and retina. High expression was also found in the primordia of various tissues, such as the olfactory epithelium, epithelium of the vomeronasal organ, enamel epithelium of teeth, anterior and intermediate lobes of the pituitary, epithelium of the inner ear, and sensory ganglia, including trigeminal and dorsal root ganglia. In addition, SemaF was expressed in lung and kidney. In adult mice, SemaF expression was markedly decreased, with very low expression in several restricted regions of the brain, including the hippocampus. Inagaki et al. (1995) suggested that SemaF functions in forming the neural network during development.
Simmons et al. (1998) had previously identified a partial human SEMAF cDNA encoded within the cri-du-chat (123450) critical region on chromosome 5p. By 5-prime RACE of human placenta RNA, they obtained a full-length SEMAF cDNA. The deduced 1,074-amino acid protein has a calculated molecular mass of 120 kD. It has an N-terminal signal sequence, followed by a 484-amino acid SEMA domain, an approximately 400-amino acid domain with 7 type-1 thrombospondin (see 188060) repeats, a transmembrane domain, and an 81-amino acid cytoplasmic domain. Northern blot analysis detected transcripts of approximately 9.6 and 15 kb in all 16 adult human tissues examined. SEMAF was also weakly expressed in fetal brain, lung, and kidney, but not in fetal liver. In situ hybridization of embryonic mouse brain detected Semaf in the ventricular zone of the anterior telencephalic vesicle at embryonic day 12.5. Expression was detected in thalamus and in the ventricular zones of cortex, stratum, and pallidum, but not hippocampus, by embryonic day 13.5.
By sequencing clones obtained from a size-fractionated human hippocampus cDNA library, Nagase et al. (2000) obtained a partial SEMA4C clone, which they called KIAA1739. RT-PCR ELISA detected very high SEMA4C expression in whole adult brain and spinal cord, as well as in all specific brain regions examined. High expression was also detected in adult heart and ovary and in fetal brain and liver. Lower SEMA4C expression was detected in all other peripheral tissues examined, with lowest expression in testis.
Using in situ hybridization, Maier et al. (2011) showed that Sema4c and a related semaphorin, Sema4g (618991), were expressed in neurons of developing mouse cerebellum. Specifically, Sema4c was expressed in granule cells and Bergmann glia, and Sema4g was expressed in Purkinje cells, in developing mouse cerebellar cortex.
Simmons et al. (1998) determined that the SEMA4C gene spans more than 200 kb.
By sequencing a YAC contig, Simmons et al. (1998) mapped the SEMA4C gene to chromosome 5p15.3, within the cri-du-chat critical region. They mapped the mouse Sema4c gene to chromosome 15.
Wu et al. (2007) found that expression of Sema4c was induced during differentiation of mouse C2C12 cells in culture and during repair of skeletal muscle injury in rats. Overexpression of human SEMA4C in C2C12 cells accelerated myotube formation, increased expression of muscle-specific proteins, and increased phosphorylation of p38 (MAPK14; 600289), a positive regulator of myogenic differentiation. Overexpression of SEMA4C did not cause activation of other signaling pathways involved in myogenic progression. Knockdown of Sema4c or chemical inhibition of p38 inhibited C2C12 differentiation. Wu et al. (2007) concluded that SEMA4C promotes terminal myogenic differentiation in a p38-dependent manner.
Using an in vitro binding assay, Maier et al. (2011) showed that mouse Sema4c and Sema4g bound to plexin-B2 receptor (PLXNB2; 604293) in cell culture and on mouse cerebellar sections. Plxnb2 was the only B-type receptor expressed in cerebellar granule cells in developing cerebellum, suggesting that Sema4c and Sema4g were ligands of Plxnb2 in cerebellum.
Maier et al. (2011) found that about a third of Sema4c -/- mice had exencephaly, a failure of neural tube closure leading to neonatal lethality. Sema4c -/- mice that bypassed exencephaly were viable and fertile and showed no obvious behavioral defects. However, all Sema4c -/- mice had cerebellar abnormalities and distinct pigmentation defects. The extent of defects was lower in Sema4c +/- mice, which express about 50% of wildtype Sema4c protein levels, indicating a potential haploinsufficiency effect. In contrast to Sema4c mice, Sema4g -/- mice exhibited normal embryonic development and were viable and fertile with no overt phenotypes or cerebellar abnormalities. Sema4c -/- Sema4g -/- double-knockout mice had enhanced cerebellar phenotypes, indicating that Sema4c and Sema4g acted in parallel as ligands for Plxnb2. Knockout analysis confirmed that Sema4c and Sema4g acted as Plxnb2 ligands in a common genetic pathway, with Sema4c playing a more dominant role that Sema4g in mediating Plxnb2-dependent cerebellar morphogenesis. Further analysis demonstrated that Sema4c and Sema4g promoted migration of granule cell precursors in a Plxnb2-dependent manner.
Inagaki, S., Furuyama, T., Iwahashi, Y. Identification of a member of mouse semaphorin family. FEBS Lett. 370: 269-272, 1995. [PubMed: 7656991] [Full Text: https://doi.org/10.1016/0014-5793(95)00850-9]
Maier, V., Jolicoeur, C., Rayburn, H., Takegahara, N., Kumanogoh, A., Kikutani, H., Tessier-Lavigne, M., Wurst, W., Friedel, R. H. Semaphorin 4C and 4G are ligands of Plexin-B2 required in cerebellar development. Molec. Cell. Neurosci. 46: 419-431, 2011. Note: Erratum: Molec. Cell. Neurosci. 125: 103837 only, 2023. [PubMed: 21122816] [Full Text: https://doi.org/10.1016/j.mcn.2010.11.005]
Nagase, T., Kikuno, R., Hattori, A., Kondo, Y., Okumura, K., Ohara, O. Prediction of the coding sequences of unidentified human genes, XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 347-355, 2000. [PubMed: 11214970] [Full Text: https://doi.org/10.1093/dnares/7.6.347]
Simmons, A. D., Puschel, A. W., McPherson, J. D., Overhauser, J., Lovett, M. Molecular cloning and mapping of human semaphorin F from the cri-du-chat candidate interval. Biochem. Biophys. Res. Commun. 242: 685-691, 1998. [PubMed: 9464278] [Full Text: https://doi.org/10.1006/bbrc.1997.8027]
Wu, H., Wang, X., Liu, S., Wu, Y., Zhao, T., Chen, X., Zhu, L., Wu, Y., Ding, X., Peng, X., Yuan, J., Wang, X., Fan, W., Fan, M. Sema4C participates in myogenic differentiation in vivo and in vitro through the p38 MAPK pathway. Europ. J. Cell Biol. 86: 331-344, 2007. [PubMed: 17498836] [Full Text: https://doi.org/10.1016/j.ejcb.2007.03.002]