DIS3L2 ribonuclease degrades terminal-uridylated RNA to ensure oocyte maturation and female fertility

During oocyte development in mice, transcripts accumulate in the growth phase and are subsequently degraded during maturation. At the transition point between growth and maturation, oocytes have an intact nucleus or germinal vesicle (GV), and terminal uridylation labels RNA for degradation in meiosis I. By profiling the transcriptome using single-oocyte long-read PacBio RNA sequencing, we document that a small cohort of mRNAs are polyadenylated after terminal uridylation in GV oocytes [designated uridylated-poly(A) RNA]. Because DIS3L2 ribonuclease is known to degrade uridylated transcripts, we established oocyte-specific Dis3l2 knockout mice (Dis3l2(cKO)). Upon DIS3L2 depletion, uridylated-poly(A) RNAs remain intact which increases their abundance, and they predominate in the transcriptome of Dis3l2(cKO) oocytes. The abundance of uridylated-poly(A) RNA in Dis3l2(cKO) oocytes arises not only from insufficient degradation, but also from the stabilizing effect of subsequent polyadenylation. Uridylated-poly(A) RNAs have shorter poly(A) tails and their translation activity decreases in Dis3l2(cKO) oocytes. Almost all Dis3l2(cKO) oocytes arrest at the GV stage, and female mice are infertile. Our study demonstrates multiple fates for RNA after terminal uridylation and highlights the role of DIS3L2 ribonuclease in safeguarding the transcriptome and ensuring female fertility.

Automated summary

During oocyte development in mice, transcripts accumulate in the growth phase and are subsequently degraded during maturation. In this study, the researchers identified a small cohort of mRNAs that are polyadenylated after terminal uridylation in GV oocytes. They found that DIS3L2 ribonuclease plays a critical role in degrading uridylated transcripts and maintaining the stability of the transcriptome, as demonstrated by oocyte-specific Dis3l2 knockout mice. The study also revealed the impact of DIS3L2 depletion on oocyte development, leading to female infertility.