Tyrosine phosphorylation of p190 RhoGAP by Fyn regulates oligodendrocyte differentiation

During development of the central nervous system, oligodendrocyte progenito r cells differentiate into mature myelinating cells. The molecular signals that promote this process, however, are not well defined. One molecule that has been implicated in oligodendrocyte differentiation is the Src family k inase Fyn. In order to probe the function of Fyn in this system, a yeast tw o hybrid screen was performed. Using Fyn as bait, p190 RhoGAP was isolated in the screen of an oligodendrocyte cDNA library. Coimmunoprecipitation and in vitro binding assays verified that p190 RhoGAP bound to the Fyn SH2 dom ain. Phosphorylation of p190 required active Fyn tyrosine kinase and was in creased threefold upon differentiation of primary oligodendrocytes. Moreove r, complex formation between p190 and p120 RasGAP occurred in differentiate d oligodendrocytes. p190 RhoGAP activity is known to regulate the RhoGDP:Rh oGTP ratio. Indeed, expression of dominant negative Rho in primary oligoden drocytes caused a hyperextension of processes. Conversely, constitutively a ctivated Rho caused reduced process formation. These findings define a path way in which Fyn activity regulates the phosphorylation of p190, leading to an increase in RhoGAP activity with a subsequent increase in RhoGDP, which in turn, regulates the morphological changes that accompany oligodendrocyt e differentiation. (C) 2001 John Wiley & Sons, Inc.