Loss of protein-tyrosine phosphatase α (PTPα) increases proliferation and delays maturation of oligodendrocyte progenitor cells.
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.
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ABSTRACT: After inflammation-induced demyelination, such as in the disease multiple sclerosis, endogenous remyelination often fails. However, in animal models of demyelination induced with toxins, remyelination can be quite robust. A significant difference between inflammation-induced and toxin-induced demyelination is the response of local cells within the lesion, including astrocytes, oligodendrocytes, microglia/macrophages, and NG2+ cells, which respond to inflammatory stimuli with increased extracellular matrix (ECM) protein and chondroitin sulfate proteoglycan (CSPG) production and deposition. Here, we summarize current knowledge of ECM changes in demyelinating lesions, as well as oligodendrocyte responses to aberrant ECM proteins and CSPGs after various types of demyelinating insults. The discovery that CSPGs act through the receptor protein tyrosine phosphatase sigma (PTPσ) and the Rho-ROCK pathway to inhibit oligodendrocyte process extension and myelination, but not oligodendrocyte differentiation (Pendleton et al., Experimental Neurology (2013) vol. 247, pp. 113-121), highlights the need to better understand the ECM changes that accompany demyelination and their influence on oligodendrocytes and effective remyelination.Experimental Neurology 11/2013; 251. DOI:10.1016/j.expneurol.2013.10.017 · 4.62 Impact Factor
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ABSTRACT: Fibrotic lung diseases represent a diverse group of progressive and often fatal disorders with limited treatment options. Although the pathogenesis of these conditions remains incompletely understood, receptor type protein tyrosine phosphatase α (PTP-α encoded by PTPRA) has emerged as a key regulator of fibroblast signaling. We previously reported that PTP-α regulates cellular responses to cytokines and growth factors through integrin-mediated signaling and that PTP-α promotes fibroblast expression of matrix metalloproteinase 3, a matrix-degrading proteinase linked to pulmonary fibrosis. Here, we sought to determine more directly the role of PTP-α in pulmonary fibrosis. Mice genetically deficient in PTP-α (Ptpra(-/-)) were protected from pulmonary fibrosis induced by intratracheal bleomycin, with minimal alterations in the early inflammatory response or production of TGF-β. Ptpra(-/-) mice were also protected from pulmonary fibrosis induced by adenoviral-mediated expression of active TGF-β1. In reciprocal bone marrow chimera experiments, the protective phenotype tracked with lung parenchymal cells but not bone marrow-derived cells. Because fibroblasts are key contributors to tissue fibrosis, we compared profibrotic responses in wild-type and Ptpra(-/-) mouse embryonic and lung fibroblasts. Ptpra(-/-) fibroblasts exhibited hyporesponsiveness to TGF-β, manifested by diminished expression of αSMA, EDA-fibronectin, collagen 1A, and CTGF. Ptpra(-/-) fibroblasts exhibited markedly attenuated TGF-β-induced Smad2/3 transcriptional activity. We conclude that PTP-α promotes profibrotic signaling pathways in fibroblasts through control of cellular responsiveness to TGF-β.American Journal Of Pathology 03/2014; DOI:10.1016/j.ajpath.2014.01.016 · 4.60 Impact Factor
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ABSTRACT: This review surveys the contributions of protein tyrosine phosphatases (PTPs) to maintenance and differentiation of stem and progenitor cells. A diverse family of PTPs acts at multiple steps of signaling cascades and cellular locales. Their activities as signaling modifiers provide another layer of integration of signaling pathways, which functionally link to the cellular activity and ultimately converge into the regulation of stem and progenitor cell fates. The development of agents targeting PTPs is a growing endeavor that will benefit stem cell biology and offer promising therapeutic strategies.Seminars in Cell and Developmental Biology 09/2014; 37. DOI:10.1016/j.semcdb.2014.09.012 · 5.97 Impact Factor