SRSF10 regulates oligodendrocyte differentiation during mouse central nervous system development by modulating pre-mRNA splicing.

Abstract

We characterized the role and regulation mechanism of a pre-mRNA splicing factor, SRSF10, in the development of oligodendrocyte lineage cells (OLCs) and the myelination process during mouse central nervous system (CNS) development. We found that depletion of SRSF10 specifically in OLCs induces hypomyelination and a decrease in OLCs in the developing mouse CNS, whereas depletion of SRSF10 only in differentiated OLCs does not significantly affect these processes. More detailed in vivo and in vitro analyses revealed that SRSF10 primarily regulates the earlier differentiation stages of OLCs, while the proliferation and apoptosis of OLCs were not affected. Mechanistically, RNA-seq and RIP-Seq transcript analyses identified a series of genes whose alternative splicing (AS) was directly regulated by SRSF10. Among these genes, compensating for the AS phenotype of Myo5a using antisense oligonucleotides (ASOs) reversed the inhibition of OLCs differentiation induced by SRSF10 depletion. In summary, we revealed for the first time that SRSF10 is a key regulator in the early differentiation of OLCs, likely via modulating the AS patterns of target genes such as Myo5a. This research provides significant implications for understanding OLC development and exploring potential therapeutic strategies for dysmyelination-related diseases.