Ythdf m6A Readers Function Redundantly during Zebrafish Development

Cell Rep. 2020 Dec 29;33(13):108598. doi: 10.1016/j.celrep.2020.108598.


During the maternal-to-zygotic transition (MZT), multiple mechanisms precisely control massive decay of maternal mRNAs. N6-methyladenosine (m6A) is known to regulate mRNA decay, yet how this modification promotes maternal transcript degradation remains unclear. Here, we find that m6A promotes maternal mRNA deadenylation. Yet, genetic loss of m6A readers Ythdf2 and Ythdf3 did not impact global maternal mRNA clearance, zygotic genome activation, or the onset of gastrulation, challenging the view that Ythdf2 alone is critical to developmental timing. We reveal that Ythdf proteins function redundantly during zebrafish oogenesis and development, as double Ythdf2 and Ythdf3 deletion prevented female gonad formation and triple Ythdf mutants were lethal. Finally, we show that the microRNA miR-430 functions additively with methylation to promote degradation of common transcript targets. Together these findings reveal that m6A facilitates maternal mRNA deadenylation and that multiple pathways and readers act in concert to mediate these effects of methylation on RNA stability.

Keywords: RNA modifications; YTHDF readers; deadenylation; embryonic development; m(6)A RNA methylation; mRNA decay; maternal transcript clearance; maternal-to-zygotic transition; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Knockout Techniques
  • Methylation
  • MicroRNAs / physiology*
  • Oogenesis
  • RNA Stability*
  • RNA, Messenger, Stored / metabolism*
  • RNA-Binding Proteins / physiology*
  • Zebrafish / embryology
  • Zebrafish / physiology*
  • Zebrafish Proteins / physiology*
  • Zygote / metabolism


  • 3' Untranslated Regions
  • MicroRNAs
  • Mirn430 microRNA, zebrafish
  • RNA, Messenger, Stored
  • RNA-Binding Proteins
  • Ythdf2 protein, zebrafish
  • Zebrafish Proteins
  • N-methyladenosine
  • Adenosine