Semaphorin-3A

Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.^[5][6][7]

SEMA3A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1Q47, 4GZ8, 4GZA
Identifiers
Aliases	SEMA3A, COLL1, HH16, Hsema-I, Hsema-III, SEMA1, SEMAD, SEMAIII, SEMAL, SemD, coll-1, semaphorin 3A
External IDs	OMIM: 603961; MGI: 107558; HomoloGene: 31358; GeneCards: SEMA3A; OMA:SEMA3A - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q21.11 Start 83,955,777 bp[1] End 84,492,724 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 A1 Start 13,175,381 bp[2] End 13,652,533 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium epithelium of colon cartilage tissue ventricular zone ganglionic eminence muscle layer of sigmoid colon gonad testicle sural nerve gastric mucosa Top expressed in outer enamel epithelium medial vestibular nucleus cervical loop genital tubercle lumbar subsegment of spinal cord fossa left lung lobe epithelium of lens tail of embryo olfactory tubercle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function chemorepellent activity semaphorin receptor binding neuropilin binding Cellular component extracellular region dendrite extracellular space axon integral component of plasma membrane Biological process sympathetic ganglion development negative regulation of axon extension cell differentiation ventral trunk neural crest cell migration regulation of axon extension involved in axon guidance semaphorin-plexin signaling pathway involved in neuron projection guidance negative chemotaxis neural crest cell migration involved in sympathetic nervous system development sympathetic nervous system development facioacoustic ganglion development dendrite morphogenesis trigeminal ganglion development neuron migration semaphorin-plexin signaling pathway involved in axon guidance regulation of heart rate nervous system development axon guidance multicellular organism development sympathetic neuron projection guidance neural crest cell migration involved in autonomic nervous system development branchiomotor neuron axon guidance gonadotrophin-releasing hormone neuronal migration to the hypothalamus axonogenesis involved in innervation dichotomous subdivision of terminal units involved in salivary gland branching facial nerve structural organization olfactory bulb development motor neuron axon guidance axonal fasciculation negative regulation of epithelial cell migration nerve development trigeminal nerve structural organization axon extension involved in axon guidance semaphorin-plexin signaling pathway sympathetic neuron projection extension positive regulation of male gonad development sensory system development apoptotic process negative regulation of neuron projection development negative regulation of axon extension involved in axon guidance positive regulation of neuron migration neural crest cell migration positive regulation of cell migration positive regulation of JNK cascade basal dendrite arborization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10371 20346 Ensembl ENSG00000075213 ENSMUSG00000028883 UniProt Q14563 O08665 RefSeq (mRNA) NM_006080 NM_001243072 NM_001243073 NM_009152 RefSeq (protein) NP_006071 NP_001230001 NP_001230002 NP_033178 Location (UCSC) Chr 7: 83.96 – 84.49 Mb Chr 5: 13.18 – 13.65 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[7]

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.^[8][9][10] 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.^[11]

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.^[12]

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.^[7][13]

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.^[14] This expression is greatest pre-symptomatically corresponding to ALS progression in which fast-fatigable fiber denervation precedes clinical symptoms.^[15] 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.^[14]

References

1. GRCh38: Ensembl release 89: ENSG00000075213 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000028883 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Kolodkin AL, Matthes DJ, Goodman CS (Jan 1994). "The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules". Cell. 75 (7): 1389–99. doi:10.1016/0092-8674(93)90625-Z. PMID 8269517. S2CID 21047504.
6. Püschel AW, Adams RH, Betz H (Jun 1995). "Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension". Neuron. 14 (5): 941–8. doi:10.1016/0896-6273(95)90332-1. PMID 7748561.
7. "Entrez Gene: SEMA3A sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A".
8. Moret F, Renaudot C, Bozon M, Castellani V (December 2007). "Semaphorin and neuropilin co-expression in motoneurons sets axon sensitivity to environmental semaphorin sources during motor axon pathfinding". Development. 134 (24): 4491–501. doi:10.1242/dev.011452. PMID 18039974.
9. Vieira JM, Schwarz Q, Ruhrberg C (May 2007). "Selective requirements for NRP1 ligands during neurovascular patterning". Development. 134 (10): 1833–43. doi:10.1242/dev.002402. PMC 2702678. PMID 17428830.
10. Sharma A, Verhaagen J, Harvey AR (2012). "Receptor complexes for each of the Class 3 Semaphorins". Frontiers in Cellular Neuroscience. 6: 28. doi:10.3389/fncel.2012.00028. PMC 3389612. PMID 22783168.
11. Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, Giraudo E (2009). "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. doi:10.1172/JCI36308. PMC 2769187. PMID 19809158.
12. 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. doi:10.3389/fncel.2014.00328. PMC 4209881. PMID 25386118.
13. Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X, Burstein DE, Kohtz DS (November 2004). "A role for semaphorin 3A signaling in degeneration of hippocampal neurons during Alzheimer's disease". J. Neurochem. 91 (3): 716–36. doi:10.1111/j.1471-4159.2004.02766.x. PMID 15485501. S2CID 25337688.
14. De Winter F, Vo T, Stam FJ, Wisman LA, Bär PR, Niclou SP, van Muiswinkel FL, Verhaagen J (2006). "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. doi:10.1016/j.mcn.2006.03.002. PMID 16677822. S2CID 466902.
15. Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P (April 2000). "Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases". J. Neurosci. 20 (7): 2534–42. doi:10.1523/JNEUROSCI.20-07-02534.2000. PMC 6772256. PMID 10729333.

Further reading

• Schmidt EF, Strittmatter SM (2007). "The CRMP Family of Proteins and Their Role in Sema3A Signaling". Semaphorins: Receptor and Intracellular Signaling Mechanisms. Advances in Experimental Medicine and Biology. Vol. 600. pp. 1–11. doi:10.1007/978-0-387-70956-7_1. ISBN 978-0-387-70955-0. PMC 2853248. PMID 17607942.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Chen H, Chédotal A, He Z, Goodman CS, Tessier-Lavigne M (1997). "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. doi:10.1016/S0896-6273(00)80371-2. PMID 9331348. S2CID 17985062.
• Takahashi T, Nakamura F, Jin Z, Kalb RG, Strittmatter SM (1999). "Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors". Nat. Neurosci. 1 (6): 487–93. doi:10.1038/2203. PMID 10196546. S2CID 38320889.
• Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM (1999). "Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors". Cell. 99 (1): 59–69. doi:10.1016/S0092-8674(00)80062-8. PMID 10520994. S2CID 18167425.
• Castellani V, De Angelis E, Kenwrick S, Rougon G (2003). "Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A". EMBO J. 21 (23): 6348–57. doi:10.1093/emboj/cdf645. PMC 136949. PMID 12456642.
• Eastwood SL, Law AJ, Everall IP, Harrison PJ (2003). "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. doi:10.1038/sj.mp.4001233. PMID 12610647. S2CID 22705053.
• Rieger J, Wick W, Weller M (2003). "Human malignant glioma cells express semaphorins and their receptors, neuropilins and plexins". Glia. 42 (4): 379–89. doi:10.1002/glia.10210. PMID 12730958. S2CID 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 (2003). "Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function". Nature. 424 (6947): 391–7. Bibcode:2003Natur.424..391S. doi:10.1038/nature01784. PMID 12879061. S2CID 33858142.
• Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ, Mercurio AM (2003). "Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells". Cancer Res. 63 (17): 5230–3. PMID 14500350.
• Catalano A, Caprari P, Rodilossi S, Betta P, Castellucci M, Casazza A, Tamagnone L, Procopio A (2004). "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. doi:10.1096/fj.03-0513fje. PMID 14656993. S2CID 40257983.
• Bagnard D, Sainturet N, Meyronet D, Perraut M, Miehe M, Roussel G, Aunis D, Belin MF, Thomasset N (2004). "Differential MAP kinases activation during semaphorin3A-induced repulsion or apoptosis of neural progenitor cells". Mol. Cell. Neurosci. 25 (4): 722–31. doi:10.1016/j.mcn.2003.12.007. PMID 15080899. S2CID 25408613.
• Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X, Burstein DE, Kohtz DS (2005). "A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease". J. Neurochem. 91 (3): 716–36. doi:10.1111/j.1471-4159.2004.02766.x. PMID 15485501. S2CID 25337688.
• Marzioni D, Tamagnone L, Capparuccia L, Marchini C, Amici A, Todros T, Bischof P, Neidhart S, Grenningloh G, Castellucci M (2005). "Restricted innervation of uterus and placenta during pregnancy: evidence for a role of the repelling signal Semaphorin 3A". Dev. Dyn. 231 (4): 839–48. doi:10.1002/dvdy.20178. PMID 15517571. S2CID 33880938.
• Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD (2005). "Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins". Science. 307 (5707): 265–8. Bibcode:2005Sci...307..265G. doi:10.1126/science.1105416. PMID 15550623. S2CID 36470855.
• Kashiwagi H, Shiraga M, Kato H, Kamae T, Yamamoto N, Tadokoro S, Kurata Y, Tomiyama Y, Kanakura Y (2005). "Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A". Blood. 106 (3): 913–21. doi:10.1182/blood-2004-10-4092. PMID 15831706. S2CID 16121509.
• Tannemaat MR, Korecka J, Ehlert EM, Mason MR, van Duinen SG, Boer GJ, Malessy MJ, Verhaagen J (2007). "Human neuroma contains increased levels of semaphorin 3A, which surrounds nerve fibers and reduces neurite extension in vitro". J. Neurosci. 27 (52): 14260–4. doi:10.1523/JNEUROSCI.4571-07.2007. PMC 6673446. PMID 18160633.

External links

• SEMA3A human gene location in the UCSC Genome Browser.
• SEMA3A human gene details in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: O08665 (Mouse Semaphorin-3A) at the PDBe-KB.