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J. Cell Biol. 167 (2): 365-375

Copyright © 2004 by the Rockefeller University Press.


Article

Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development

Holly Colognato1,2, Shwetha Ramachandrappa1,2, Inger M. Olsen1,2, , and Charles ffrench-Constant1,2,3

1 Department of Pathology, University of Cambridge, Cambridge CB21QP, England, UK
2 Centre for Brain Repair, University of Cambridge, Cambridge CB21QP, England, UK
3 Department of Medical Genetics, University of Cambridge, Cambridge CB21QP, England, UK

Correspondence to Holly Colognato: colognato{at}pharm.sunysb.edu

Abstract: 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 {alpha}6ß1 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 {alpha}Vß3-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.

H. Colognato's present address is Dept. of Pharmacology, State University of New York at Stony Brook, Stony Brook, NY 11794.

Abbreviations used in this paper: Csk, COOH-terminal Src kinase; ERK, extracellular signal–related kinase; FN, fibronectin; GalC, galactocerebroside; Lm2, laminin-2; MAG, myelin-associated glycoprotein; MBP, myelin basic protein; NRG, neuregulin; PDGF{alpha}R, PDGF{alpha} receptor; PDL, poly-D-lysine; SFK, Src family kinase; siRNA, small interfering RNA.


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