| Summary: | Oligodendrocytes are specialized cells of the central nervous system (CNS) that are responsible for axonal myelination. They are derived from precursors termed oligodendrocyte progenitor cells (OPCs). In OPCs, the signal transduction pathways that regulate self-renewal versus differentiation remain poorly defined. The tyrosine kinase Fyn plays a critical role in oligodendrocyte differentiation and myelination in the CNS. However, the upstream molecules that regulate Fyn activity in these cells are not well characterized. In these studies, I utilized two model systems, the rat CG4 oligodendroglial cell line and a genetically modified mouse with germline PTPα knock-out, to investigate the role of protein tyrosine phosphatase alpha (PTPα) in OPC differentiation. My results demonstrate that PTPα is required for OPC differentiation and functions in at least two distinct phases during the lifespan and maturation of OPCs. Firstly, upon induction of OPC differentiation, Fyn activation and signaling are significantly reduced in the absence of PTPα, as measured by enhanced negative regulatory phosphorylation of Fyn and reduced activation or inhibition of Fyn downstream effectors such as focal adhesion kinase, Rac1, Cdc42, and Rho. Furthermore, myelination is defective in the brains of PTPα-/- mice, suggesting that OPC maturation requires PTPα-mediated signal transduction cascades. Secondly, OPCs must cease proliferation in order for differentiation to occur, and I found that PTPα-/- cells exhibit enhanced proliferation, as well as decreased cell cycle exit and increased survival. Interestingly, the activities of Ras and the Rho GTPases Rac1, Cdc42, and Rho were significantly increased, and p27 protein levels were significantly decreased, in the absence of PTPα. Moreover, Fyn is responsible for Rho inactivation and p27 accumulation. In conclusion, I propose that PTPα negatively regulates OPC proliferation and promotes cell cycle exit, causing cell fate commitment. Subsequently, PTPα positively regulates and promotes differentiation and maturation. These functions of PTPα in OPC proliferation and differentiation processes are mainly exerted through PTPα-mediated dephosphorylation and activation of Fyn to induce the process-specific regulation of common and distinct Fyn effector molecules.
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