TY - JOUR T1 - EXOSC10 mediated RNA degradation sculpts the transcriptome during oocyte growth-to-maturation transition JF - bioRxiv DO - 10.1101/663377 SP - 663377 AU - Di Wu Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/06/06/663377.abstract N2 - Disorders of ovulation account for 40% of female infertility to which improper oocyte maturation contributes significantly. During mammalian oogenesis, oocytes accumulate substantial amounts of RNA in the growth phase, the majority of which is degraded during subsequent maturation. The growth-to-maturation transition begins with nuclear envelope breakdown, which is designated germinal vesicle breakdown (GVBD) in oocytes. A successful growth-to-maturation transition is essential for subsequent ovulation, fertilization and embryogenesis. Previous studies documented important characteristics of this transition, including cAMP-PKA signaling, SUMOylation and CDK phosphorylation. However, the concomitant changes in the oocyte transcriptome during GVBD remained unclear. Here, we report that an RNA exosome associated RNase, EXOSC10, degrades poly(A) RNA to facilitate the oocyte growth-to-maturation transition. We establish an oocyte-specific conditional knockout of Exosc10 in mice using CRISPR/Cas9 and document female subfertility. We further determine that oocyte growth is not affected, but maturation is delayed or blocked with failed GVBD in EXOSC10 depleted oocytes. We performed single oocyte RNA-seq at GV, GVBD and MII stages and employed ERCC spike-in normalization to compare transcriptomes among these stages. scRNA-seq documents dysregulated transcriptomes in mutant oocytes, and many up regulated RNAs that encode proteins important for protein trafficking, cell cycle and RNA metabolism. We find impaired early to late endosome maturation and overall disruption of endoplasmic reticulum and lysosomes, which confirm defects in the endomembrane system. In addition, CDK1 phosphorylation fails to change from inhibitory to active, which blocked lamina phosphorylation and disassembly in the mutant oocytes. Collectively, we propose that EXOSC10 promotes the growth-to-maturation transition in oocytes by degrading growth-phase factors and sculpting the transcriptome to the maturation phase of oogenesis. ER -