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

Abstract

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.

Histology-associated transcriptomic heterogeneity in ovarian folliculogenesis revealed by quantitative single-cell RNA-sequencing for tissue sections with DRaqL

“…S9C), and successfully detected splice isoforms in many genes, including H1foo, Lsm14b, Rac1, Trp53bp1, Oosp1 , and Parl . For example, the minor splice isoforms of Lsm14b, Rac1 , and Trb53bp1 , which are regulated by ESRP1 in oocytes (Yu et al 2021), were detected in this analysis. Moreover, in Serf2 and Cox6b2 , we detected oocyte-specific minor splice isoforms.…”

“…Next, we conducted an exon–exon junction analysis of the oocytes in the alcohol-fixed sections, because there is growing evidence of the importance of alternative splicing in oocytes for meiotic progression, oocyte growth and maturation, and female fertility (Tang et al 2009; Do et al 2018; Kasowitz et al 2018; Cheng et al 2020; Li et al 2020; Yu et al 2021) (Supplemental Fig. S10).…”

In Vivo and In Vitro Matured Oocytes From Mice of Advanced Reproductive Age Exhibit Alternative Splicing Processes for Mitochondrial Oxidative Phosphorylation

“…In mammalian oocytes, conserved stagespecific transcript variants indicate that alternative pre-mRNA splicing plays a crucial role in the accurate control of the maternal transcriptome (32,33). For example, ESRP1 is involved in the AS programming of oocyte mRNA processing and the ESRP1 deletion-induced pre-mRNA splicing changes in spindle organization-related genes that lead to female infertility (34). Depletion of the nuclear m6A reader YTHDC1 causes extensive alternative polyadenylation and the 3′-UTR length is altered in oocytes, thus resulting in female sterility (35).…”

BCAS2 is involved in alternative splicing and mouse oocyte development

“…Increasing evidence suggests that AS plays a critical role in mouse oogenesis and female fertility. For example, ESRP1, an epithelial‐specific RNA‐binding protein, was reported to be involved in mouse oogenesis and female fertility by participating in the AS regulation of mRNA 15 . The RNA‐binding protein serine/arginine‐rich splicing factor 3 was also reported to be involved in the maintenance of the integrity of the transcriptome in mouse oocytes via AS 16 .…”

“…For example, ESRP1, an epithelial-specific RNA-binding protein, was reported to be involved in mouse oogenesis and female fertility by participating in the AS regulation of mRNA. 15 The RNA-binding protein serine/argininerich splicing factor 3 was also reported to be involved in the maintenance of the integrity of the transcriptome in mouse oocytes via AS. 16 Due to the limitations of materials and methods, how AS regulates mouse oogenesis and female fertility remains largely unknown.…”