Semaphorin 7A promotes axon outgrowth through integrins and MAPKs.
Striking parallels exist between immune and nervous system cellular signalling mechanisms. Molecules originally shown to be critical for immune responses also serve neuronal functions, and similarly neural guidance cues can modulate immune function. We show here that semaphorin 7A (Sema7A), a membrane-anchored member of the semaphorin family of guidance proteins previously known for its immunomodulatory effects, can also mediate neuronal functions. Unlike many other semaphorins, which act as repulsive guidance cues, Sema7A enhances central and peripheral axon growth and is required for proper axon tract formation during embryonic development. Unexpectedly, Sema7A enhancement of axon outgrowth requires integrin receptors and activation of MAPK signalling pathways. These findings define a previously unknown biological function for semaphorins, identify an unexpected role for integrins and integrin-dependent intracellular signalling in mediating semaphorin responses, and provide a framework for understanding and interfering with Sema7A function in both immune and nervous systems.
Pasterkamp
R Jeroen
RJ
Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
Peschon
Jacques J
JJ
Spriggs
Melanie K
MK
Kolodkin
Alex L
AL
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D058851:GPI-Linked Proteins; D017353:Gene Deletion; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D021122:Protein Subunits; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D058851:GPI-Linked Proteins; D016023:Integrins; D021122:Protein Subunits; D011991:Receptors, Virus; C118753:SEMA7A protein, human; C485571:Sema7a protein, mouse; D039961:Semaphorins; C112038:VESPR semaphorin receptor; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat; D020928:Mitogen-Activated Protein Kinases