m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition

The N6-methyladenosine (m6A) modification facilitates maternally driven clearance of zebrafish maternal mRNAs through the m6A-binding protein Ythdf2, ensuring proper and timely embryonic development. Maternally derived messenger RNAs (mRNAs) are used for the early development of the embryo until transcription starts in the embryo, when maternal mRNAs are degraded. But how is this controlled? Chuan He and colleagues find that zebrafish maternal mRNAs carry a specific modification, N6-methyladenosine (m6A), which targets them for recognition by an m6A-binding protein, Ythdf2. This action triggers the degradation of the maternal mRNA so that the embryonic developmental program can take over. The maternal-to-zygotic transition (MZT) is one of the most profound and tightly orchestrated processes during the early life of embryos, yet factors that shape the temporal pattern of vertebrate MZT are largely unknown. Here we show that over one-third of zebrafish maternal messenger RNAs (mRNAs) can be N6-methyladenosine (m6A) modified, and the clearance of these maternal mRNAs is facilitated by an m6A-binding protein, Ythdf2. Removal of Ythdf2 in zebrafish embryos decelerates the decay of m6A-modified maternal mRNAs and impedes zygotic genome activation. These embryos fail to initiate timely MZT, undergo cell-cycle pause, and remain developmentally delayed throughout larval life. Our study reveals m6A-dependent RNA decay as a previously unidentified maternally driven mechanism that regulates maternal mRNA clearance during zebrafish MZT, highlighting the critical role of m6A mRNA methylation in transcriptome switching and animal development.