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Sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A
Protein SEMA3A PDB 1q47.png
PDB rendering based on 1q47.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols SEMA3A ; COLL1; HH16; Hsema-I; Hsema-III; SEMA1; SEMAD; SEMAIII; SEMAL; SemD; coll-1
External IDs OMIM603961 MGI107558 HomoloGene31358 GeneCards: SEMA3A Gene
RNA expression pattern
PBB GE SEMA3A 206805 at tn.png
More reference expression data
Species Human Mouse
Entrez 10371 20346
Ensembl ENSG00000075213 ENSMUSG00000028883
UniProt Q14563 O08665
RefSeq (mRNA) NM_006080 NM_001243072
RefSeq (protein) NP_006071 NP_001230001
Location (UCSC) Chr 7:
83.59 – 84.12 Mb
Chr 5:
13.4 – 13.6 Mb
PubMed search [1] [2]

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


This 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 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.[3]

Semaphorin-3A is a secreted protein, or chemorepulser, secreted by surrounding tissues to guide migrating cells and axons in the developing nervous system of an organism which is critical for the precise formation of neurons and vasculature. Semaphorins, which are short range inhibitory proteins that act as axonal growth cone guidance molecules, are synthesized by neurons during axon pathfinding. Repulsive guidance cue semaphorin-3A (Sema3A) is a gene of the semaphorin family and is expressed by motorneurons to control motor axonal pathfinding. 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. During nervous system development, guidance cues, such as Semaphorin-3A induce the collapse and paralysis of neuronal growth cones. This repulsive cue for developing axons are signaled through receptor complexes containing Neuropilin-1 (NRP1), which is a protein receptor in active neurons.[4][5]

The first of the CRMP proteins, CRMP2, was identified as an intracellular messenger required for the growth cone-collapse induced by semaphorin 3A.

Clinical significance[edit]

Increased expression of this protein 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.[6][3]

Additionally, the terminal Schwann cells of ALS mice (SOD1 mutant) express Sema3A at fast-fatigable fiber neuromuscular junctions greater than wild-type mice.[7] This expression is greatest pre-symptomatically corresponding to ALS progression in which fast-fatigable fiber denervation precedes clinical symptoms.[8] Because Sema3A is involved in growth cone collapse and axon pruning and repulsion, it potentially holds a causal relationship to synaptic weakening and denervation that precedes motor neuron apoptosis in ALS.[7]


  1. ^ 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. 
  2. ^ 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. 
  3. ^ a b c "Entrez Gene: SEMA3A sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A". 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X et al. (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. 
  7. ^ a b De Winter F, Vo T, Stam FJ, Wisman LA, Bär PR, Niclou SP et al. (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. 
  8. ^ 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. PMID 10729333. 

Further reading[edit]

  • Schmidt EF, Strittmatter SM (2007). "The CRMP family of proteins and their role in Sema3A signaling". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology 600: 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. 
  • 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. 
  • Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG et al. (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. 
  • 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/ PMID 12610647. 
  • 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. 
  • Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F et al. (2003). "Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function". Nature 424 (6947): 391–7. doi:10.1038/nature01784. PMID 12879061. 
  • Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ et al. (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 et al. (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. 
  • Bagnard D, Sainturet N, Meyronet D, Perraut M, Miehe M, Roussel G et al. (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. 
  • Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X et al. (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. 
  • Marzioni D, Tamagnone L, Capparuccia L, Marchini C, Amici A, Todros T et al. (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. 
  • Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J et al. (2005). "Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins". Science 307 (5707): 265–8. doi:10.1126/science.1105416. PMID 15550623. 
  • Kashiwagi H, Shiraga M, Kato H, Kamae T, Yamamoto N, Tadokoro S et al. (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. 
  • Tannemaat MR, Korecka J, Ehlert EM, Mason MR, van Duinen SG, Boer GJ et al. (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. PMID 18160633. 

External links[edit]