Abstract
Mechanisms regulating mammalian meiotic progression are poorly understood. Here we identify mouse YTHDC2 as a critical component of this regulation. A screen yielded a mutant, “ketu”, with male and female sterility caused by a Ythdc2 missense mutation. Mutant germ cells enter meiosis but proceed prematurely to aberrant metaphase and apoptosis. ketu phenocopies mutants lacking MEIOC, a YTHDC2 partner. YTHDC2 is cytoplasmic and a YTH domain solution structure reveals conservation of a hydrophobic N6-methyladenosine recognition pocket, consistent with roles in post-transcriptional regulation. Orthologs are present throughout metazoans, but are structurally diverged in nematodes and, more dramatically, in Drosophilidae, where Bgcn is a biochemically distinct descendant of a Ythdc2 gene duplication. We also uncover similarity between MEIOC and Bam, a Bgcn partner unique to schizophoran flies. We propose that regulation of gene expression by the YTHDC2-MEIOC complex is an evolutionarily ancient strategy for controlling the germline transition from mitosis to meiosis.