ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2
- Memorial Sloan Kettering Cancer Center, United States
- Weill Cornell Medicine, United States
Abstract
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.
Data availability
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ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE108044).
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YTHDC2 regulates spermatogenesis through promoting the translation of N6-methyladenosine-modified RNAPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE98085).
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Cellular source and mechanisms of high transcriptome complexity in the mammalian testis (RNA-Seq cells)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE43717).
Article and author information
Author details
Christopher D Lima
Funding
Howard Hughes Medical Institute
- M Rhyan Puno
- Christopher D Lima
- Scott Keeney
National Aeronautics and Space Administration (NNX14AH50G 15-15Omni2-0063)
- Cem Meydan
- Christopher E Mason
Bill and Melinda Gates Foundation (OPP1151054)
- Cem Meydan
- Christopher E Mason
Cycle for Survival
- Nathalie Lailler
Marie-Josée and Henry R. Kravis Center for Molecular Oncology
- Nathalie Lailler
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37 HD035455)
- Kathryn V Anderson
Human Frontier Science Program
- Devanshi Jain
National Cancer Institute (P30 CA008748)
- Nathalie Lailler
National Institute of General Medical Sciences (R35 GM118080)
- M Rhyan Puno
- Christopher D Lima
Starr Cancer Consortium (I9-A9-071)
- Cem Meydan
- Christopher E Mason
Bert L and N Kuggie Vallee Foundation
- Cem Meydan
- Christopher E Mason
WorldQuant Foundation
- Cem Meydan
- Christopher E Mason
Pershing Square Sohn Cancer Research Alliance
- Cem Meydan
- Christopher E Mason
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments conformed to regulatory standards and were approved by the Memorial Sloan Kettering Cancer Center (MSKCC) Institutional Animal Care and Use Committee under protocol #01-03-007.
Copyright
© 2018, Jain et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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