SRSF2 is a key player in orchestrating the directional migration and differentiation of MyoD progenitors during skeletal muscle development.

Abstract

SRSF2 plays a dual role, functioning both as a transcriptional regulator and a key player in alternative splicing. The absence of Srsf2 in MyoD + progenitors resulted in perinatal mortality in mice, accompanied by severe skeletal muscle defects. SRSF2 deficiency disrupts the directional migration of MyoD progenitors, causing them to disperse into both muscle and non-muscle regions. Single-cell RNA-sequencing analysis revealed significant alterations in Srsf2-deficient myoblasts, including a reduction in extracellular matrix components, diminished expression of genes involved in ameboid-type cell migration and cytoskeleton organization, mitosis irregularities, and premature differentiation. Notably, one of the targets regulated by Srsf2 is the serine/threonine kinase Aurka. Knockdown of <i>Aurka</i> led to reduced cell proliferation, disrupted cytoskeleton, and impaired differentiation, reflecting the effects seen with <i>Srsf2</i> knockdown. Crucially, the introduction of exogenous Aurka in <i>Srsf2</i>-knockdown cells markedly alleviated the differentiation defects caused by <i>Srsf2</i> knockdown. Furthermore, our research unveiled the role of Srsf2 in controlling alternative splicing within genes associated with human skeletal muscle diseases, such as <i>BIN1</i>, <i>DMPK</i>, <i>FHL1</i>, and <i>LDB3</i>. Specifically, the precise knockdown of the <i>Bin1</i> exon17-containing variant, which is excluded following <i>Srsf2</i> depletion, profoundly disrupted C2C12 cell differentiation. In summary, our study offers valuable insights into the role of SRSF2 in governing MyoD progenitors to specific muscle regions, thereby controlling their differentiation through the regulation of targeted genes and alternative splicing during skeletal muscle development.