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ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2.

Devanshi Jain | M Rhyan Puno | Cem Meydan | Nathalie Lailler | Christopher E Mason | Christopher D Lima | Kathryn V Anderson | Scott Keeney
eLife | 2018

Mechanisms regulating mammalian meiotic progression are poorly understood. Here we identify mouse YTHDC2 as a critical component. A screen yielded a sterile mutant, 'ketu', caused by a Ythdc2 missense mutation. Mutant germ cells enter meiosis but proceed prematurely to aberrant metaphase and apoptosis, and display defects in transitioning from spermatogonial to meiotic gene expression programs. ketu phenocopies mutants lacking MEIOC, a YTHDC2 partner. Consistent with roles in post-transcriptional regulation, YTHDC2 is cytoplasmic, has 3'→5' RNA helicase activity in vitro, and has similarity within its YTH domain to an N6-methyladenosine recognition pocket. Orthologs are present throughout metazoans, but are diverged in nematodes and, more dramatically, Drosophilidae, where Bgcn is descended from 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 YTHDC2-MEIOC is an evolutionarily ancient strategy for controlling the germline transition into meiosis.

Pubmed ID: 29360036

Associated grants

  • Agency: NASA, United States
    Id: NNX14AH50G 15-15Omni2-0063
  • Agency: Bill and Melinda Gates Foundation, International
    Id: OPP1151054
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NCI NIH HHS, United States
    Id: P30 CA008748
  • Agency: NICHD NIH HHS, United States
    Id: R37 HD035455
  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM118080

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