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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-formingcells of the central nervous system, promote either differentiationand survival or proliferation by amplification of growth factorsignaling. Here, we report that the Src family kinases (SFKs)Fyn and Lyn regulate each of these distinct integrin-drivenbehaviors. Fyn associates with 6ß1 and is requiredto amplify platelet-derived growth factor survival signaling,to promote myelin membrane formation, and to switch neuregulinsignaling from a phosphatidylinositol 3-kinase to a mitogen-activatedprotein kinase pathway (thereby changing the response from proliferationto differentiation). However, earlier in the lineage Lyn, notFyn, is required to drive Vß3-dependent progenitorproliferation. The two SFKs respond to integrin ligation bydifferent mechanisms: Lyn, by increased autophosphorylationof a catalytic tyrosine; and Fyn, by reduced Csk phosphorylationof the inhibitory COOH-terminal tyrosine. These findings illustratehow different SFKs can act as effectors for specific cell responsesduring development within a single cell lineage, and, furthermore,provide a molecular mechanism to explain similar region-specifichypomyelination in laminin- and Fyn-deficient mice.
H. Colognato's present address is Dept. of Pharmacology, StateUniversity 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-associatedglycoprotein; MBP, myelin basic protein; NRG, neuregulin; PDGFR,PDGF receptor; PDL, poly-D-lysine; SFK, Src family kinase; siRNA,small interfering RNA.
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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 
