Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase

In the central nervous system, myelination of axons occurs when oligodendro cyte progenitors undergo terminal differentiation and initiate process form ation and axonal ensheathment. Although it is hypothesized that neuron-olig odendrocyte contact initiates this process, the molecular signals are not k nown. Here we find that Fyn tyrosine kinase activity is upregulated very ea rly during oligodendrocyte progenitor cell differentiation. Concomitant wit h this increase is the appearance of several tyrosine phosphorylated protei ns present only in differentiated cells. The increased tyrosine kinase acti vity is specific to Fyn, as other Src family members are not active in olig odendrocytes. To investigate the function of Fyn activation on differentiat ion, we used Src family tyrosine kinase inhibitors. PP1 and PP2, in culture s of differentiating oligodendrocyte progenitors. Treatment of progenitors with these compounds prevented activation of Fyn and reduced process extens ion and myelin membrane formation. This inhibition was reversible and not o bserved with related inactive analogues. A similar effect was observed when a dominant negative Fyn was introduced in progenitor cells. These findings strongly suggest that activation of Fyn is an essential signaling componen t for the morphological differentiation of oligodendrocytes.