The Journal of biological chemistry, 2012-04, Vol.287 (15), p.12529-12540
2012
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Loss of Protein-tyrosine Phosphatase α (PTPα) Increases Proliferation and Delays Maturation of Oligodendrocyte Progenitor Cells
- Ist Teil von
- The Journal of biological chemistry, 2012-04, Vol.287 (15), p.12529-12540
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. Background: Development of mature myelinating oligodendrocytes requires the co-ordinated migration, proliferation, and differentiation of oligodendrocyte progenitor cells (OPCs). Results: OPCs lacking PTPα show enhanced proliferation and altered activity and/or expression of several signaling molecules. Conclusion: PTPα-dependent signaling limits OPC proliferation. Significance: This provides insight into the molecular events that promote the cessation of proliferation to position OPCs for differentiation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9258eISSN: 1083-351XDOI: 10.1074/jbc.M111.312769Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3321002
- Format
- –
- Schlagworte
- Animals, Apoptosis, Brain - cytology, Brain - enzymology, Brain - growth & development, cdc42 GTP-Binding Protein - metabolism, Cell Cycle, Cell Proliferation, Cell Signaling, Cell Survival, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p27 - genetics, Cyclin-Dependent Kinase Inhibitor p27 - metabolism, Fibroblast Growth Factor 2 - physiology, Fyn, Gene Knockout Techniques, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Neural Stem Cells - metabolism, Neural Stem Cells - physiology, Neuropeptides - metabolism, Oligodendrocytes, Oligodendroglia - physiology, Phosphotyrosine Signaling, Platelet-Derived Growth Factor - physiology, Protein Phosphatase, Proto-Oncogene Proteins c-fyn - metabolism, PTPRA, rac GTP-Binding Proteins - metabolism, rac1 GTP-Binding Protein, Rats, Receptor-Like Protein Tyrosine Phosphatases, Class 4 - genetics, Receptor-Like Protein Tyrosine Phosphatases, Class 4 - metabolism, rho GTP-Binding Proteins - antagonists & inhibitors, rho GTP-Binding Proteins - metabolism, Signal Transduction, Spheroids, Cellular - physiology, Tyrosine-protein Phosphatase (Tyrosine Phosphatase), Up-Regulation