m(6)A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition

The maternal-to-zygotic transition (MZT) is one of the most profound and 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 N(6)-methyladenosine (m(6)A) modified, and the clearance of these maternal mRNAs is facilitated by an m(6)A-binding protein, Ythdf2. Removal of Ythdf2 in zebrafish embryos decelerates the decay of m(6)A-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 m(6)A-dependent RNA decay as a previously unidentified maternally driven mechanism that regulates maternal mRNA clearance during zebrafish MZT, highlighting the critical role of m(6)A mRNA methylation in transcriptome switching and animal development.