Abstract
Proper follicle development is very important for the production of mature oocytes, which is essential for the maintenance of female fertility. This complex biological process requires precise gene regulation. The most abundant modification of mRNA, N6-methyladenosine (m6A), is involved in many RNA metabolism processes, including RNA splicing, translation, stability, and degradation. Here, we report that m6A plays essential roles during oocyte and follicle development. Oocyte-specific inactivation of the key m6A methyltransferase Mettl3 with Gdf9-Cre caused DNA damage accumulation in oocytes, defective follicle development, and abnormal ovulation. Mechanistically, combined RNA-seq and m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) data from oocytes revealed, that we found METTL3 targets Itsn2 for m6A modification and then enhances its stability to influence the oocytes meiosis. Taken together, our findings highlight the crucial roles of mRNA m6A modification in follicle development and coordination of RNA stabilization during oocyte growth.
Highlights
In mice, a few days after birth, a restricted number of oocytes within primordial follicles serve as the source of mature eggs for reproduction [1]
According to the sequencing data, we identified 3256 (45.8%) maternal RNAs expressed in germinal vesicle (GV) oocytes that contained m6A modifications, suggesting that the function of m6A in oocytes has been underestimated
Through a combination of RNA-seq and MeRIPseq data, we found that m6A-modified transcripts showed significantly lower expression upon Mettl3 deletion than transcripts without m6A (Fig. 4E)
Summary
A few days after birth, a restricted number of oocytes within primordial follicles serve as the source of mature eggs for reproduction [1]. Through follicle recruitment or activation, resting primordial follicles are recruited into the growing follicle stage featuring oocyte growth and proliferation of somatic granulosa cells [2] At this stage, oocytes grow rapidly with transcription of a large number of mRNAs that are crucial for subsequent oocyte meiotic maturation and early embryo development. [34, 35], and YTHDF2, which regulates maternal mRNA decay in 1G, H) Together, these results demonstrate that Mettl in oocytes the MII stage [29]. By knocking down Mettl in GV primordial follicles to the activated growing follicle stage, but oocytes from mice, oocyte maturation and early embryo devel- mainly functions in the process of growing follicle development. We found that METTL3-mediated m6A modification regulates showed that more DSBs were produced in the secondary follicles of the Mettl3Gdf cKO mice than in those of the WT mice (Fig. 2C, D). Mettl3Gdf cKO mice showed a significantly higher apoptosis signal in secondary and antral follicle than WT mice (Fig. 2E, F)
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