Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development.
Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.
Colognato
Holly
H
Department of Pathology, University of Cambridge, Cambridge CB21QP, England, UK. colognato@pharm.sunysb.edu
Ramachandrappa
Shwetha
S
Olsen
Inger M
IM
ffrench-Constant
Charles
C
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D039121:Integrin alpha6beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009186:Myelin Sheath / Q000737:chemistry; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013234:Stem Cells; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism*
D039121:Integrin alpha6beta1; D016023:Integrins; D007797:Laminin; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; C494957:FYN protein, human; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases