Abstract
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.
Highlights
Development of mature myelinating oligodendrocytes requires the co-ordinated migration, proliferation, and differentiation of oligodendrocyte progenitor cells (OPCs)
We used cultured primary OPCs isolated from wild type (WT) and PTP␣-null (PTP␣Ϫ/Ϫ) mouse embryos to investigate the function of PTP␣ in progenitor cells as a regulator of proliferation, cell cycle exit, and survival
Because Fyn is an important substrate of PTP␣ and we have shown that Fyn activity is decreased in proliferating phosphatase ␣ (PTP␣)Ϫ/Ϫ primary OPCs [21], we determined if Fyn is involved in PTP␣-mediated signaling that inhibits CG4 OPC proliferation and promotes cell cycle exit
Summary
Development of mature myelinating oligodendrocytes requires the co-ordinated migration, proliferation, and differentiation of oligodendrocyte progenitor cells (OPCs). PTP␣-deficient mouse OPCs and rat CG4 cells have decreased Fyn and increased Ras, Cdc, Rac, and Rho activities, and reduced expression of the Cdk inhibitor p27Kip. We propose that PTP␣-Fyn signaling negatively regulates OPC proliferation by down-regulating Ras and Rho, leading to p27Kip accumulation and cell cycle exit. The development of oligodendrocyte progenitor cells (OPCs) into mature OLs is a complex process requiring cessa-. Various growth factors have been shown to regulate OL development, such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) [1] that co-operatively promote selfrenewal and survival and inhibit differentiation of OPCs [2,3,4]. We investigated the role of PTP␣, and PTP␣-mediated Fyn signaling, in proliferation and cell cycle regulation of OPCs
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