Loss of Protein-tyrosine Phosphatase (PTP ) Increases Proliferation and Delays Maturation of Oligodendrocyte Progenitor Cells

Department of Pathology, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2012; 287(15):12529-40. DOI: 10.1074/jbc.M111.312769
Source: PubMed


Tightly controlled termination of proliferation determines when oligodendrocyte progenitor cells (OPCs) can initiate differentiation
and mature into myelin-forming cells. Protein-tyrosine phosphatase α (PTPα) promotes OPC differentiation, but its role in
proliferation is unknown. Here we report that loss of PTPα enhanced in vitro proliferation and survival and decreased cell cycle exit and growth factor dependence of OPCs but not neural stem/progenitor
cells. PTPα−/− mice have more oligodendrocyte lineage cells in embryonic forebrain and delayed OPC maturation. On the molecular level, PTPα-deficient
mouse OPCs and rat CG4 cells have decreased Fyn and increased Ras, Cdc42, Rac1, and Rho activities, and reduced expression
of the Cdk inhibitor p27Kip1. Moreover, Fyn was required to suppress Ras and Rho and for p27Kip1 accumulation, and Rho inhibition
in PTPα-deficient cells restored expression of p27Kip1. We propose that PTPα-Fyn signaling negatively regulates OPC proliferation
by down-regulating Ras and Rho, leading to p27Kip1 accumulation and cell cycle exit. Thus, PTPα acts in OPCs to limit self-renewal
and facilitate differentiation.

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    • "For example, major substrates of PTPα are the Src family kinases (Pallen, 2003). In primary OPCs, PTPα acts through the Src kinase Fyn to negatively regulate the activity of Rho, Rac1, and Cdc42, thereby limiting proliferation and promoting differentiation (Pallen, 2003; Wang et al., 2012). In contrast , in differentiating oligodendrocytes, PTPα positively regulates Rac1 and Cdc42, while negatively regulating Rho signaling, which promotes cytoskeletal rearrangements necessary for process extension and maturation (Wang et al., 2009, 2012). "
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