Semaphorin-3A Explained

Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.^{[1] [2] [3]}

Function

The SEMA3A gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted Semaphorin-3A protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development.

Semaphorin-3A is secreted by neurons and surrounding tissue to guide migrating cells and axons in the developing nervous system. Axon pathfinding is the process by which neurons follow very precise paths, sends out axons, and react to specific chemical environments to reach the correct endpoint. The guidance is critical for the precise formation of neurons and the surrounding vasculature. Guidance cues, such as Sema3A, induce the collapse and paralysis of neuronal growth cones during development of the nervous system.

This guidance cue for axons of neurons is signaled through receptor complexes containing Neuropilin-1 (NRP1) and a co-receptor.^{[4] [5] [6]} One of the first identified intracellular messenger required for the growth cone-collapse induced by Sema3A is the CRMP protein called CRMP2.

In addition to its role in the nervous system, Sema3A also acts as an inhibitor of angiogenesis, the process by which new blood vessels develop.^[7]

Clinical significance

The protein semaphorin-3A is highly expressed in scar tissue after traumatic central nervous system injuries, such as spinal cord injury. Semaphorin-3A, and the other class 3 semaphorins, contributes to the failure of neuronal regeneration after CNS injury by regulating axonal re-growth, re-myelination, re-vascularisation, and the immune response.^[8]

Increased expression of semaphorin-3A is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease.^[9]

Additionally, the terminal Schwann cells of amyotrophic lateral sclerosis (ALS) mice (SOD1 mutant) express semaphorin-3A at fast-fatigable fiber neuromuscular junctions greater than wild-type mice.^[10] This expression is greatest pre-symptomatically corresponding to ALS progression in which fast-fatigable fiber denervation precedes clinical symptoms.^[11] Because semaphorin-3A is involved in growth cone collapse, axon pruning, and repulsion, it potentially holds a causal relationship to synaptic weakening and denervation that precedes motor neuron apoptosis in ALS.^[10]

Further reading

• Book: Schmidt EF, Strittmatter SM . The CRMP Family of Proteins and Their Role in Sema3A Signaling . Semaphorins: Receptor and Intracellular Signaling Mechanisms . 600 . 1–11 . 2007 . 17607942 . 2853248 . 10.1007/978-0-387-70956-7_1 . 978-0-387-70955-0 . Advances in Experimental Medicine and Biology . registration .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Res. . 6 . 9 . 791–806 . 1997 . 8889548 . 10.1101/gr.6.9.791 . free .
• Chen H, Chédotal A, He Z, Goodman CS, Tessier-Lavigne M . Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III . Neuron . 19 . 3 . 547–59 . 1997 . 9331348 . 10.1016/S0896-6273(00)80371-2 . 17985062 . free .
• Takahashi T, Nakamura F, Jin Z, Kalb RG, Strittmatter SM . Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors . Nat. Neurosci. . 1 . 6 . 487–93 . 1999 . 10196546 . 10.1038/2203 . 38320889 .
• Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM . Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors . Cell . 99 . 1 . 59–69 . 1999 . 10520994 . 10.1016/S0092-8674(00)80062-8 . 18167425 . free .
• Castellani V, De Angelis E, Kenwrick S, Rougon G . Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A . EMBO J. . 21 . 23 . 6348–57 . 2003 . 12456642 . 136949 . 10.1093/emboj/cdf645 .
• Eastwood SL, Law AJ, Everall IP, Harrison PJ . The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology . Mol. Psychiatry . 8 . 2 . 148–55 . 2003 . 12610647 . 10.1038/sj.mp.4001233 . 22705053 .
• Rieger J, Wick W, Weller M . Human malignant glioma cells express semaphorins and their receptors, neuropilins and plexins . Glia . 42 . 4 . 379–89 . 2003 . 12730958 . 10.1002/glia.10210 . 45643250 .
• Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F, Zammataro L, Primo L, Tamagnone L, Logan M, Tessier-Lavigne M, Taniguchi M, Püschel AW, Bussolino F . Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function . Nature . 424 . 6947 . 391–7 . 2003 . 12879061 . 10.1038/nature01784 . 2003Natur.424..391S . 33858142 .
• Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ, Mercurio AM . Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells . Cancer Res. . 63 . 17 . 5230–3 . 2003 . 14500350 .
• Catalano A, Caprari P, Rodilossi S, Betta P, Castellucci M, Casazza A, Tamagnone L, Procopio A . Cross-talk between vascular endothelial growth factor and semaphorin-3A pathway in the regulation of normal and malignant mesothelial cell proliferation . FASEB J. . 18 . 2 . 358–60 . 2004 . 14656993 . 10.1096/fj.03-0513fje . free . 40257983 .
• Bagnard D, Sainturet N, Meyronet D, Perraut M, Miehe M, Roussel G, Aunis D, Belin MF, Thomasset N . Differential MAP kinases activation during semaphorin3A-induced repulsion or apoptosis of neural progenitor cells . Mol. Cell. Neurosci. . 25 . 4 . 722–31 . 2004 . 15080899 . 10.1016/j.mcn.2003.12.007 . 25408613 .
• Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X, Burstein DE, Kohtz DS . A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease . J. Neurochem. . 91 . 3 . 716–36 . 2005 . 15485501 . 10.1111/j.1471-4159.2004.02766.x . 25337688 . free .
• Marzioni D, Tamagnone L, Capparuccia L, Marchini C, Amici A, Todros T, Bischof P, Neidhart S, Grenningloh G, Castellucci M . Restricted innervation of uterus and placenta during pregnancy: evidence for a role of the repelling signal Semaphorin 3A . Dev. Dyn. . 231 . 4 . 839–48 . 2005 . 15517571 . 10.1002/dvdy.20178 . 33880938 .
• Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD . Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins . Science . 307 . 5707 . 265–8 . 2005 . 15550623 . 10.1126/science.1105416 . 2005Sci...307..265G . 36470855 . free .
• Kashiwagi H, Shiraga M, Kato H, Kamae T, Yamamoto N, Tadokoro S, Kurata Y, Tomiyama Y, Kanakura Y . Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A . Blood . 106 . 3 . 913–21 . 2005 . 15831706 . 10.1182/blood-2004-10-4092 . 16121509 .
• Tannemaat MR, Korecka J, Ehlert EM, Mason MR, van Duinen SG, Boer GJ, Malessy MJ, Verhaagen J . Human neuroma contains increased levels of semaphorin 3A, which surrounds nerve fibers and reduces neurite extension in vitro . J. Neurosci. . 27 . 52 . 14260–4 . 2007 . 18160633 . 10.1523/JNEUROSCI.4571-07.2007 . 6673446 . free .

Notes and References

1. Kolodkin AL, Matthes DJ, Goodman CS . The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules . Cell . 75 . 7 . 1389–99 . Jan 1994 . 8269517 . 10.1016/0092-8674(93)90625-Z . 21047504 .
2. Püschel AW, Adams RH, Betz H . Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension . Neuron . 14 . 5 . 941–8 . Jun 1995 . 7748561 . 10.1016/0896-6273(95)90332-1 . free .
3. Web site: Entrez Gene: SEMA3A sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A.
4. Moret F, Renaudot C, Bozon M, Castellani V . Semaphorin and neuropilin co-expression in motoneurons sets axon sensitivity to environmental semaphorin sources during motor axon pathfinding . Development . 134 . 24 . 4491–501 . December 2007 . 18039974 . 10.1242/dev.011452 . free .
5. Vieira JM, Schwarz Q, Ruhrberg C . Selective requirements for NRP1 ligands during neurovascular patterning . Development . 134 . 10 . 1833–43 . May 2007 . 17428830 . 2702678 . 10.1242/dev.002402 .
6. Sharma A, Verhaagen J, Harvey AR . Receptor complexes for each of the Class 3 Semaphorins . Frontiers in Cellular Neuroscience . 6 . 28 . 22783168 . 3389612 . 10.3389/fncel.2012.00028 . 2012. free .
7. Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, Giraudo E . Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. . The Journal of Clinical Investigation . 119 . 11 . 3356–72 . 19809158 . 10.1172/JCI36308 . 2769187 . 2009.
8. Mecollari. V. Nieuwenhuis. B. Verhaagen. J. 2014. A perspective on the role of class III semaphorin signaling in central nervous system trauma. Frontiers in Cellular Neuroscience. 8. 328. 10.3389/fncel.2014.00328. 4209881. 25386118. free.
9. Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X, Burstein DE, Kohtz DS . A role for semaphorin 3A signaling in degeneration of hippocampal neurons during Alzheimer's disease . J. Neurochem. . 91 . 3 . 716–36 . November 2004 . 15485501 . 10.1111/j.1471-4159.2004.02766.x . 25337688 . free .
10. De Winter F, Vo T, Stam FJ, Wisman LA, Bär PR, Niclou SP, van Muiswinkel FL, Verhaagen J . The expression of the chemorepellent Semaphorin 3A is selectively induced in terminal Schwann cells of a subset of neuromuscular synapses that display limited anatomical plasticity and enhanced vulnerability in motor neuron disease . Mol. Cell. Neurosci. . 32 . 1–2 . 102–17 . 2006 . 16677822 . 10.1016/j.mcn.2006.03.002 . 466902 .
11. Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P . Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases . J. Neurosci. . 20 . 7 . 2534–42 . April 2000 . 10729333 . 10.1523/JNEUROSCI.20-07-02534.2000. 6772256 . free .