Alternative titles; symbols
HGNC Approved Gene Symbol: SEMA3F
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:50,155,058-50,189,075 (from NCBI)
The semaphorins are a family of proteins that are involved in signaling. All the family members have a secretion signal, a 500-amino acid sema domain, and 16 conserved cysteine residues (Kolodkin et al., 1993). Sequence comparisons have grouped the secreted semaphorins into 3 general classes, all of which also have an immunoglobulin domain. The semaphorin III family, consisting of human semaphorin III (SEMA3A; 603961), chicken collapsin, and mouse semaphorins A, D, and E, all have a basic domain at the C terminus. Chicken collapsin contributes to path finding by axons during development by inhibiting extension of growth cones (Luo et al., 1993) through an interaction with a collapsin response mediator protein of relative molecular mass 62K (CRMP62) (Goshima et al., 1995), a putative homolog of an axonal guidance associated UNC33 gene product (601168). SEMA3F is a secreted member of the semaphorin III family.
Xiang et al. (1996) isolated a novel human semaphorin, which they termed semaphorin III/F, from a region of the 3p21.3 region involved in homozygous deletions in 2 small cell lung cancer (SCLC) cell lines. The gene was expressed as a 3.8-kb transcript in a variety of cell lines and tissues. It was detected as early as embryonic day 10 in mouse development. There was high expression in mammary gland, kidney, fetal brain, and lung and lower expression in heart and liver. Although there was reduced expression of the gene in several SCLC lines, no mutations were found. The new gene had characteristics of a secreted member of the semaphorin III family, with 52% identity with mouse semaphorin E and 49% identity with chicken collapsin/semaphorin D.
Lerman and Minna (2000) detected expression of SEMA3F in some lung cancer cell lines tested but found no mutations in the gene. They proposed that SEMA3F should be considered for functional tumor suppressor gene and methylation analyses.
Most striatal and cortical interneurons arise from the basal telencephalon, later segregating to their respective targets. Marin et al. (2001) demonstrated that migrating cortical interneurons avoid entering the striatum because of a chemorepulsive signal composed at least in part of semaphorin-3A and semaphorin-3F. Migrating interneurons expressing neuropilins, receptors for semaphorins, are directed to the cortex; those lacking them go to the striatum. Loss of neuropilin function increases the number of interneurons that migrate into the striatum. Marin et al. (2001) concluded that their observations reveal a mechanism by which neuropilins mediate sorting of distinct neuronal populations into different brain structures, and provide evidence that, in addition to guiding axons, these receptors also control neuronal migration in the central nervous system.
Tran et al. (2009) demonstrated that the secreted semaphorin Sema3F is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F, and its holoreceptor components neuropilin-2 (NPN2; 602070) and plexin A3 (PLEXA3; 300022), exhibit increased dentate gyrus granule cell and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn2-null brain slices cortical layer V and dentate gyrus granule cells exhibit increased miniature excitatory postsynaptic current frequency. In contrast, a distinct Sema3A (603961)-Npn1 (602069)/PlexA4 (604280) signaling cascade controls basal dendritic arborization in layer V cortical neurons, but does not influence spine morphogenesis or distribution. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn2 to apical dendrites and of Npn1 to all dendrites of cortical pyramidal neurons. Therefore, Sema3F signaling controls spine distribution along select dendritic processes, and distinct secreted semaphorin signaling events orchestrate central nervous system connectivity through the differential control of spine morphogenesis, synapse formation, and elaboration of dendritic morphology.
By genomic sequence analysis, Lerman and Minna (2000) determined that the 28-kb SEMA3F gene contains 18 exons.
Sekido et al. (1996) localized the SEMA3F and SEMA3B (601281) genes to 3p21.3.
Bielenberg et al. (2004) found that SEMA3F was markedly downregulated in highly metastatic human melanoma cell lines in vitro and in vivo. When these cells were transfected with SEMA3F and implanted into mice, the resultant tumors did not metastasize and resembled benign nevi characterized by large areas of apoptosis, diminished vascularity, inhibition of hyperplasia in overlying epidermal cells, and encapsulated tumor borders delineated by thick layers of fibroblasts and collagen matrix. In vitro, tumor cells expressing SMA3F had a diminished capacity to adhere and migrate on fibronectin. Consistent with semaphorin-mediated chemorepulsion of neurons, tumor cells expressing SEMA3F were chemorepulsive for vascular and lymphatic endothelial cells expressing the SEMA3F receptor neuropilin 2 (NRP2; 602070), and the repulsive activity was abrogated by NRP2 RNA interference. Bielenberg et al. (2004) concluded that SEMA3F is a potent metastasis inhibitor that targets both tumor and stromal cells.
Bielenberg, D. R., Hida, Y., Shimizu, A., Kaipainen, A., Kreuter, M., Kim, C. C., Klagsbrun, M. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J. Clin. Invest. 114: 1260-1271, 2004. [PubMed: 15520858] [Full Text: https://doi.org/10.1172/JCI21378]
Goshima, Y., Nakamura, F., Strittmatter, P., Strittmatter, S. M. Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376: 509-514, 1995. [PubMed: 7637782] [Full Text: https://doi.org/10.1038/376509a0]
Kolodkin, A. L., Matthes, D. J., Goodman, C. S. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75: 1389-1399, 1993. [PubMed: 8269517] [Full Text: https://doi.org/10.1016/0092-8674(93)90625-z]
Lerman, M. I., Minna, J. D. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. Cancer Res. 60: 6116-6133, 2000. [PubMed: 11085536]
Luo, Y., Raible, D., Raper, J. A. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75: 217-227, 1993. [PubMed: 8402908] [Full Text: https://doi.org/10.1016/0092-8674(93)80064-l]
Marin, O., Yaron, A., Bagri, A., Tessier-Lavigne, M., Rubenstein, J. L. R. Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science 293: 872-875, 2001. [PubMed: 11486090] [Full Text: https://doi.org/10.1126/science.1061891]
Sekido, Y., Bader, S., Latif, F., Chen, J.-Y., Duh, F.-M., Wei, M.-H., Albanesi, J. P., Lee, C.-C., Lerman, M. I., Minna, J. D. Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc. Nat. Acad. Sci. 93: 4120-4125, 1996. [PubMed: 8633026] [Full Text: https://doi.org/10.1073/pnas.93.9.4120]
Tran, T. S., Rubio, M. E., Clem, R. L., Johnson, D., Case, L., Tessier-Lavigne, M., Huganir, R. L., Ginty, D. D., Kolodkin, A. L. Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 462: 1065-1069, 2009. [PubMed: 20010807] [Full Text: https://doi.org/10.1038/nature08628]
Xiang, R.-H., Hensel, C. H., Garcia, D. K., Carlson, H. C., Kok, K., Daly, M. C., Kerbacher, K., van den Berg, A., Veldhuis, P., Buys, C. H. C. M., Naylor S. L. Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer. Genomics 32: 39-48, 1996. [PubMed: 8786119] [Full Text: https://doi.org/10.1006/geno.1996.0074]