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Protection of p27Kip1 mRNA by quaking RNA binding proteins promotes oligodendrocyte differentiation

Abstract

The quaking (Qk) locus expresses a family of RNA binding proteins, and the expression of several alternatively spliced isoforms coincides with the development of oligodendrocytes and the onset of myelination. Quaking viable (Qkv) mice harboring an autosomal recessive mutation in this locus have uncompacted myelin in the central nervous system owing to the inability of oligodendrocytes to properly mature. Here we show that the expression of two QKI isoforms, absent from oligodendrocytes of Qkv mice, induces cell cycle arrest of primary rat oligodendrocyte progenitor cells and differentiation into oligodendrocytes. Injection of retroviruses expressing QKI into the telencephalon of mouse embryos induced differentiation and migration of multipotential neural progenitor cells into mature oligodendrocytes localized in the corpus callosum. The mRNA encoding the cyclin-dependent kinase (CDK)-inhibitor p27Kip1 was bound and stabilized by QKI, leading to an increased accumulation of p27Kip1 protein in oligodendrocytes. Our findings demonstrate that QKI is upstream of p27Kip1 during oligodendrocyte differentiation.

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Figure 1: QKI-6 and QKI-7 cause a G0/G1 cell cycle arrest in primary rat oligodendrocyte progenitors.
Figure 2: Differentiation of OPCs after expression of QKI-6 and QKI-7 isoforms.
Figure 3: QKI isoforms induce p27Kip1 upregulation by stabilizing its mRNA.
Figure 4: The areas of the corpus callosum injected with AdQKI-6 and AdQKI-7 contain elevated MBP expression.
Figure 5: Ectopic expression of QKI-6 and QKI-7 promotes oligodendrocyte glial cell fate specification and migration to the corpus callosum and caudate putamen in vivo.

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Acknowledgements

We thank N. Billon, L. Cai, C. Cepko, D. Colman, N. Gaiano, M. Loignon and M. Raff for advice, reagents and helpful discussions; and members of the laboratory, especially J. Pilotte and C.-A. Chénard, for helpful discussions. This work was supported by grants from the Multiple Sclerosis Society of Canada to S.R. and G.A. D.L. is a recipient of a Ph.D. studentship from the K.M. Hunter/Canadian Institutes of Health Research (CIHR) Foundation. A.G. holds a Ph.D. studentship from the National Cancer Institutes of Canada. S.R. is an investigator of the CIHR.

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Correspondence to Stéphane Richard.

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Supplementary Table 1

Bioinformatics analysis of QKI mRNA targets responsible for oligodendrocyte differentiation (PDF 161 kb)

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Larocque, D., Galarneau, A., Liu, HN. et al. Protection of p27Kip1 mRNA by quaking RNA binding proteins promotes oligodendrocyte differentiation. Nat Neurosci 8, 27–33 (2005). https://doi.org/10.1038/nn1359

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