Alternative splicing (AS) contributes to gene diversification, but the 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 was blocked during oocyte meiosis owing to abnormal activation of spindle assembly checkpoint and insufficiency of anaphase-promoting complex/cyclosome in Esrp1-knockout oocytes. Esrp1-knockout hampered follicular development and ovulation; eventually, premature ovarian failure occurred in six-month-old Esrp1-knockout mouse. Using single-cell RNA-seq 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, which may contribute to oocyte meiosis and female fertility in mice.
Keywords: Alternative splicing; ESRP1; Female fertility; Meiosis; Mouse; Oocyte.
© 2021. Published by The Company of Biologists Ltd.