Loss of ESRP1 blocks mouse oocyte development and leads to female infertility

Alternative splicing (AS) contributes to gene diversification, but AS program during germline development remains largely undefined. Here, we interrupted pre-mRNA splicing events controlled by epithelial splicing regulatory protein 1 (ESRP1) and found that it induced female infertility in mice. Esrp1 deletion perturbed spindle organization, chromosome alignment, and metaphase-to-anaphase transformation in oocytes. The first polar body extrusion (PBE) was blocked during oocyte meiosis due to abnormal activation of spindle assembly checkpoint (SAC) and insufficiency of anaphase-promoting complex/cyclosome (APC/C) in Esrp1-knockout oocytes. Esrp1-knockout hampered follicular development and ovulation; eventually, premature ovarian failure (POF) occurred in six-month-old Esrp1-knockout mouse. Using single-cell RNA sequencing analysis, 528 aberrant AS events of maternal mRNA transcripts were revealed and were preferentially associated with microtubule cytoskeletal organization. Notably, we found that loss of ESRP1 disturbed a comprehensive set of gene-splicing sites—including those within Trb53bp1, Rac1, Bora, Kif2c, Kif23, Ndel1, Kif3a, Cenpa, and Lsm14b—that potentially caused abnormal spindle organization. Collectively, our findings provide the first report elucidating the ESRP1- mediated AS program of maternal mRNA transcripts, may contribute to oocyte meiosis and female fertility in mice.