Abstract Splicing factor SRSF2 acts as a critical regulator for cell survival, however, it remains unknown whether SRSF2 is involved in myoblast proliferation and myogenesis. Here, knockdown of SRSF2 in myoblasts causes high rates of apoptosis and defective differentiation. Combined conditional knockout and lineage tracing approaches show that Myf5‐cre mice lacking SRSF2 die immediately at birth and exhibit a complete absence of mature myofibers. Mutant Myf5‐derived cells (tdtomato‐positive cells) are randomly scattered in the myogenic and non‐myogenic regions, indicating loss of the community effect required for skeletal muscle differentiation. Single‐cell RNA‐sequencing reveals high heterogeneity of myf5‐derived cells and non‐myogenic cells are significantly increased at the expense of skeletal muscle cells in the absence of SRSF2, reflecting altered cell fate. SRSF2 is demonstrated to regulate the entry of Myf5 cells into the myogenic program and ensures their survival by preventing precocious differentiation and apoptosis. In summary, SRSF2 functions as an essential regulator for Myf5‐derived cells to respond correctly to positional cues and to adopt their myogenic fate.
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