Inhibition of Raly promotes oligodendrocyte precursor cell differentiation and remyelination after chronic hypoperfusion

The heterogeneous nuclear ribonucleoprotein-associated protein Raly plays a role in regulating cell proliferation and metabolism in eukaryotic nerve cells. However, the biological significance of Raly in oligodendrocyte lineage progression has not been previously explored. In this study, we found that Raly expression decreased during maturation of oligodendrocyte lineage cells. Knockdown of Raly in primary oligodendrocyte progenitor cells cultured in differentiation medium resulted in a significant increase in myelin-related proteins myelin basic protein and MAG. Furthermore, injection of an adenovirus expressing Raly shRNA into the subventricular zone of mice promoted oligodendrocyte progenitor cell differentiation, restored white matter integrity, and ameliorated cognitive deficits in the bilateral common carotid artery stenosis and senescence model. We further investigated the mechanism by which Raly regulates oligodendrocyte progenitor cell differentiation. Downregulation of Raly in primary oligodendrocyte progenitor cells led to increased mRNA and protein levels of Sox10, a pivotal player in oligodendrocyte development. The stability of Sox10 mRNA was unaffected by Raly downregulation, and RNA immunoprecipitation assays showed no binding between Raly and Sox10 mRNA. Dual luciferase and chromatin immunoprecipitation assays revealed that Raly downregulated the transcription of Sox10 by binding to a site located 1200 bp upstream of the Sox10 start codon. Collectively, our findings suggest that Raly plays a crucial role in oligodendrocyte progenitor cell differentiation and negatively regulates Sox10. These results may provide new insights into therapeutic strategies for neurological disorders associated with hypomyelination.