Osterhout D J, Wolven A, Wolf R M, Resh M D, Chao M V
Molecular Neurobiology Program, Skirball Institute, New York University Medical Center, New York 10016, USA.
J Cell Biol. 1999 Jun 14;145(6):1209-18. doi: 10.1083/jcb.145.6.1209.
In the central nervous system, myelination of axons occurs when oligodendrocyte progenitors undergo terminal differentiation and initiate process formation and axonal ensheathment. Although it is hypothesized that neuron-oligodendrocyte contact initiates this process, the molecular signals are not known. Here we find that Fyn tyrosine kinase activity is upregulated very early during oligodendrocyte progenitor cell differentiation. Concomitant with this increase is the appearance of several tyrosine phosphorylated proteins present only in differentiated cells. The increased tyrosine kinase activity is specific to Fyn, as other Src family members are not active in oligodendrocytes. To investigate the function of Fyn activation on differentiation, we used Src family tyrosine kinase inhibitors, PP1 and PP2, in cultures of differentiating oligodendrocyte progenitors. Treatment of progenitors with these compounds prevented activation of Fyn and reduced process extension and myelin membrane formation. This inhibition was reversible and not observed 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 component for the morphological differentiation of oligodendrocytes.
在中枢神经系统中，当少突胶质前体细胞经历终末分化并开始形成突起和包裹轴突时，轴突发生髓鞘形成。尽管据推测神经元与少突胶质细胞的接触启动了这一过程，但分子信号尚不清楚。在这里，我们发现Fyn酪氨酸激酶活性在少突胶质前体细胞分化的早期就被上调。伴随着这种增加的是几种仅在分化细胞中出现的酪氨酸磷酸化蛋白。酪氨酸激酶活性的增加是Fyn特有的，因为其他Src家族成员在少突胶质细胞中不活跃。为了研究Fyn激活对分化的作用，我们在分化的少突胶质前体细胞培养物中使用了Src家族酪氨酸激酶抑制剂PP1和PP2。用这些化合物处理前体细胞可阻止Fyn的激活，并减少突起延伸和髓鞘膜形成。这种抑制是可逆的，且在相关的无活性类似物中未观察到。当在祖细胞中引入显性负性Fyn时，也观察到了类似的效果。这些发现强烈表明，Fyn的激活是少突胶质细胞形态分化的一个重要信号成分。
