| Oligodendrocyte differentiation is controlled by a complex network of epigenetic regulators, transcription factors, RNA binding proteins, and cell cycle regulators. The involvement of QKI, an RNA binding protein that regulates mRNA stability, splicing and transport, is only well characterized in rodent myelin development. QKI regulates oligodendrocyte differentiation by controlling in part the expression of cyclin-dependent kinase inhibitor p27 (p27Kip1), a cell cycle inhibitor, and myelin basic protein (MBP), a major myelin component. In this thesis, we first show that human glial progenitor cells readily expressed QKI-6 and QKI-7 but not QKI-5. These cells increased the expression of all three major QKI isoforms as they commit to the OPC lineage and become mature oligodendrocytes. The ectopic QKI-6 and QKI-7 expression promoted human oligodendrocyte differentiation, while QKI-5 played a negative role in this process. Second, we show that protein arginine methyl transferase 5 (PRMT5), an enzyme known to symmetrically dimethylate both QKI and MBP in vitro, was up-regulated during myelin development and indeed methylated MBP in vivo. PRMT5 deficient oligodendrocytes demonstrated impaired differentiation, which was reflected by both the morphology and the transcription factor expression profile. Together our findings implicate that QKI-6, QKI-7 and PRMT5 are promoters of oligodendrocyte differentiation, while QKI-5 is an inhibitor of the maturation process. |
