SRSF1 Maintains Sertoli Cell Proliferation and Survival by Regulating Alternative Splicing in Coordination With DDX5 and RBMX/RBMXL1

Abstract

Sertoli cells provide essential structural and nutritional support for germ cell development and play critical roles in spermatogenesis. Post‐transcriptional regulation exerts important functions in Sertoli cells. Complex alternative splicing processes exist in Sertoli cells. This study focuses on splicing factor SRSF1 to investigate its function and mechanisms in Sertoli cell development. Sertoli cell‐specific SRSF1 ablation from embryonic development arrests cell proliferation and increases apoptosis, thereby reducing Sertoli cell number, constricting the germ cell microenvironment, and causing progressive germ cell loss, ultimately resulting in male infertility. Mechanistically, SRSF1 regulates CDK pathway and Bax/Bcl2 pathway‐related gene transcription and forms spliceosomal complexes with DDX5 and RBMX/RBMXL1 to modulate AS of Cidea and Rif1, thereby governing Sertoli cell proliferation, apoptosis, and DNA damage response. This study establishes SRSF1 as a multifunctional spliceosomal hub in Sertoli cells, refining our understanding of post‐transcriptional regulation in spermatogenesis and providing potential therapeutic targets for male infertility.