Department of Pathology, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
J Biol Chem. 2012 Apr 6;287(15):12529-40. doi: 10.1074/jbc.M111.312769. Epub 2012 Feb 21.
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.
紧密控制增殖的终止决定了少突胶质前体细胞（OPC）何时能够开始分化并成熟为形成髓鞘的细胞。蛋白酪氨酸磷酸酶α（PTPα）促进 OPC 分化，但它在增殖中的作用尚不清楚。在这里，我们报告说 PTPα 的缺失增强了 OPC 的体外增殖和存活，并减少了细胞周期退出和生长因子对 OPC 的依赖性，但对神经干细胞/祖细胞没有影响。PTPα（-/-）小鼠的胚胎前脑中具有更多的少突胶质谱系细胞，并且 OPC 成熟延迟。在分子水平上，PTPα 缺陷型小鼠 OPC 和大鼠 CG4 细胞中 Fyn 的活性降低，Ras、Cdc42、Rac1 和 Rho 的活性增加，Cdk 抑制剂 p27Kip1 的表达减少。此外，Fyn 被需要抑制 Ras 和 Rho 并促进 p27Kip1 的积累，而 PTPα 缺陷型细胞中的 Rho 抑制恢复了 p27Kip1 的表达。我们提出 PTPα-Fyn 信号通过下调 Ras 和 Rho 负调控 OPC 的增殖，导致 p27Kip1 的积累和细胞周期退出。因此，PTPα 在 OPC 中起作用以限制自我更新并促进分化。
