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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- "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). "
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: CNS damage often results in demyelination of spared axons due to oligodendroglial cell death and dysfunction near the injury site. Although new oligodendroglia are generated following CNS injury and disease, the process of remyelination is typically incomplete resulting in long-term functional deficits. Chondroitin sulfate proteoglycans (CSPGs) are upregulated in CNS grey and white matter following injury and disease and are a major component of the inhibitory scar that suppresses axon regeneration. CSPG inhibition of axonal regeneration is mediated, at least in part, by the protein tyrosine phosphatase sigma (PTPσ) receptor. Recent evidence demonstrates that CSPGs inhibit OL process outgrowth, however, the means by which their effects are mediated remains unclear. Here we investigate the role of PTPσ in CSPG inhibition of OL function. We found that the CSPGs, aggrecan, neurocan and NG2 all imposed an inhibitory effect on OL process outgrowth and myelination. These inhibitory effects were reversed by degradation of CSPGs with Chondroitinase ABC prior to OL exposure. RNAi-mediated down-regulation of PTPσ reversed the inhibitory effect of CSPGs on OL process outgrowth and myelination. Likewise, CSPG inhibition of process outgrowth and myelination was significantly reduced in cultures containing PTPσ(-/-) OLs. Finally, inhibition of Rho-associated kinase (ROCK) increased OL process outgrowth and myelination during exposure to CSPGs. These results suggest that in addition to their inhibitory effects on axon regeneration, CSPGs have multiple inhibitory actions on OLs that result in incomplete remyelination following CNS injury. The identification of PTPσ as a receptor for CSPGs, and the participation of ROCK downstream of CSPG exposure, reveal potential therapeutic targets to enhance white matter repair in the damaged CNS.Experimental Neurology 04/2013; 247. DOI:10.1016/j.expneurol.2013.04.003 · 4.62 Impact Factor
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ABSTRACT: In vertebrates, the contactin (CNTN) family of neural cell recognition molecules includes six related cell adhesion molecules that play non-overlapping roles in the formation and maintenance of the nervous system. CNTN1 and CNTN2 are the prototypical members of the family and have been involved, through cis- and trans-interactions with distinct cell adhesion molecules, in neural cell migration, axon guidance, and the organization of myelin subdomains. In contrast, the roles of CNTN3-6 are less well characterized although the generation of null mice and the recent identification of a common extracellular binding partner have considerably advanced our grasp of their physiological roles in particular as they relate to the wiring of sensory tissues. In this review, we aim to present a summary of our current understanding of CNTN functions and give an overview of the challenges that lie ahead in understanding the roles these proteins play in nervous system development and maintenance.