Alternative titles; symbols
HGNC Approved Gene Symbol: PLXNA2
Cytogenetic location: 1q32.2 Genomic coordinates (GRCh38): 1:208,022,242-208,244,384 (from NCBI)
Maestrini et al. (1996) identified PLXNA2, which they called OCT, as a gene closely related to SEX (300022), a transmembrane protein with significant homology to members of the hepatocyte growth factor (HGF) receptor family. They also identified 2 other genes closely related to SEX, PLXNB1 (601053) and PLXNA1 (601055). The proteins encoded by all 4 genes contain large cytoplasmic domains characterized by a distinctive highly conserved sequence that Maestrini et al. (1996) called the SEX domain.
Suto et al. (2007) found that mouse plexin-A2 preferentially localized to pyramidal cell dendrites, but not to mossy fibers. In contrast, plexin-A4 localized to mossy fibers. Sema6a (605885) was expressed and secreted by CA3 pyramidal cells and interneurons in the stratum lacunosum-moleculare and functioned with plexin-A4 as a repressive molecule to mediate mossy fiber repulsion. Plexin-A2 attenuated Sema6a-mediated mossy fiber repulsion, possibly by sequestration of Sema6a, allowing mossy fibers to invade the suprapyramidal region of CA3. Suto et al. (2007) concluded that Sema6a, plexin-A2, and plexin-A4 regulate the laminar projection of mossy fibers in mouse hippocampus.
Using in vivo analyses in knockout mice, Tawarayama et al. (2010) showed that Sema6a and Sema6b functioned as repellents for mossy fibers to prevent abnormal projections. Repulsive activities of Sema6a and Sema6b were additive and were mediated by Plxna4 (604280). Sema6b suppressed innervation of mossy fibers into the suprapyramidal region in a dosage-dependent manner. Plxna2 attenuated mossy fiber repulsion by Sema6a and promoted growth of mossy fibers.
Crystal Structure
Janssen et al. (2010) presented crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1-SEMA4D (601866) and murine PlxnA2-Sema6A (605885)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto). These structures, together with biophysical and cellular assays of wildtype and mutant proteins, revealed that semaphorin dimers independently bind 2 plexin molecules and that signaling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signaling). The data of Janssen et al. (2010) favored a cell-cell signaling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal 7-bladed beta-propeller (sema) domains of both semaphorin and plexin, suggested that a common mode of interaction triggers all semaphorin-plexin-based signaling, while distinct insertions within or between blades of the sema domains determine binding specificity.
Nogi et al. (2010) independently reported the crystal structure of the semaphorin 6A (605885) receptor-binding fragment and the plexin A2 ligand-binding fragment in both their pre-signaling (before binding) and signaling (after complex formation) states. Before binding, the Sema6A ectodomain was in the expected face-to-face homodimer arrangement, similar to that adopted by Sema3A (603961) and Sema4D, whereas PlxnA2 was in an unexpected head-on homodimer arrangement. In contrast, the structure of the Sema6A-PlxnA2 signaling complex revealed a 2:2 heterotetramer in which the 2 Plxn2A monomers dissociated from one another and docked onto the top face of the Sema6A homodimer using the same interface as the head-on homodimer, indicating that plexins undergo 'partner exchange.' Cell-based activity measurements using mutant ligands/receptors confirmed that the Sema6A face-to-face dimer arrangement is physiologically relevant and is maintained throughout signaling events. Nogi et al. (2010) concluded that homodimer-to-heterodimer transitions of cell-surface plexin that result in a specific orientation of its molecular axis relative to the membrane may constitute the structural mechanism by which the ligand-binding signal is transmitted to the cytoplasmic region, inducing GAP domain rearrangements and activation.
By analysis of a panel of human/hamster somatic cell hybrids, Maestrini et al. (1996) mapped the OCT gene to chromosome 1. Gross (2011) mapped the PLXNA2 gene to chromosome 1q32.2 based on an alignment of the PLXNA2 sequence (GenBank BC136530) with the genomic sequence (GRCh37).
Tamagnone et al. (1999) proposed a novel nomenclature for the genes of the plexin family, which they grouped into the A, B, C, and D subfamilies; the PLXN2 gene was renamed plexin A2 by them.
Mossy fibers are the last hippocampal afferents to invade CA3, and in mouse, they do so around the time of birth. Suto et al. (2007) showed that plexin-A2 deletion in mice caused a shift of mossy fibers from the suprapyramidal region to the infra- and intrapyramidal regions. In plexin-A2 -/- plexin-A4 -/- double-knockout mice, mossy fibers were widely distributed within CA3 in a pattern similar to that seen in plexin-A4 -/- mice, suggesting that plexin-A4 has a predominant role in the laminar projection of mossy fibers. Mossy fiber synapses formed normally and were functional in plexin-A2 -/- mice.
Gross, M. B. Personal Communication. Baltimore, Md. 3/1/2011.
Janssen, B. J. C., Robinson, R. A., Perez-Branguli, F., Bell, C. H., Mitchell, K. J., Siebold, C., Jones, E. Y. Structural basis of semaphorin-plexin signalling. Nature 467: 1118-1122, 2010. [PubMed: 20877282] [Full Text: https://doi.org/10.1038/nature09468]
Maestrini, E., Tamagnone, L., Longati, P., Cremona, O., Gulisano, M., Bione, S., Tamanini, F., Neel, B. G., Toniolo, D., Comoglio, P. M. A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. Proc. Nat. Acad. Sci. 93: 674-678, 1996. [PubMed: 8570614] [Full Text: https://doi.org/10.1073/pnas.93.2.674]
Nogi, T., Yasui, N., Mihara, E., Matsunaga, Y., Noda, M., Yamashita, N., Toyofuku, T., Uchiyama, S., Goshima, Y., Kumanogoh, A., Takagi, J. Structural basis for semaphorin signalling through the plexin receptor. Nature 467: 1123-1127, 2010. [PubMed: 20881961] [Full Text: https://doi.org/10.1038/nature09473]
Suto, F., Tsuboi, M., Kamiya, H., Mizuno, H., Kiyama, Y., Komai, S., Shimizu, M., Sanbo, M., Yagi, T., Hiromi, Y., Chedotal, A., Mitchell, K. J., Manabe, T., Fujisawa, H. Interactions between plexin-A2, plexin-A4, and semaphorin 6A control lamina-restricted projection of hippocampal mossy fibers. Neuron 53: 535-547, 2007. [PubMed: 17296555] [Full Text: https://doi.org/10.1016/j.neuron.2007.01.028]
Tamagnone, L., Artigiani, S., Chen, H., He, Z., Ming, G., Song, H., Chedotal, A., Winberg, M. L., Goodman, C. S., Poo, M., Tessier-Lavigne, M., Comoglio, P. M. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99: 71-80, 1999. Note: Erratum: Cell 104: following 320, 2001. [PubMed: 10520995] [Full Text: https://doi.org/10.1016/s0092-8674(00)80063-x]
Tawarayama, H., Yoshida, Y., Suto, F., Mitchell, K. J., Fujisawa, H. Roles of semaphorin-6B and plexin-A2 in lamina-restricted projection of hippocampal mossy fibers. J. Neurosci. 30: 7049-7060, 2010. [PubMed: 20484647] [Full Text: https://doi.org/10.1523/JNEUROSCI.0073-10.2010]