METTL3-mediated mRNA N⁶-methyladenosine is required for oocyte and follicle development in mice

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.