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

  1. Devanshi Jain
  2. M Rhyan Puno
  3. Cem Meydan
  4. Nathalie Lailler
  5. Christopher E Mason
  6. Christopher D Lima
  7. Kathryn V Anderson
  8. Scott Keeney  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. 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.

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The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Devanshi Jain

    Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. M Rhyan Puno

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Cem Meydan

    Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nathalie Lailler

    Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christopher E Mason

    Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Christopher D Lima

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9163-6092
  7. Kathryn V Anderson

    Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Scott Keeney

    Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    s-keeney@ski.mskcc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1283-6417

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.

Reviewing Editor

  1. Bernard de Massy, Institute of Human Genetics, CNRS UPR 1142, France

Publication history

  1. Received: August 1, 2017
  2. Accepted: January 22, 2018
  3. Accepted Manuscript published: January 23, 2018 (version 1)
  4. Version of Record published: March 1, 2018 (version 2)

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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  1. Devanshi Jain
  2. M Rhyan Puno
  3. Cem Meydan
  4. Nathalie Lailler
  5. Christopher E Mason
  6. Christopher D Lima
  7. Kathryn V Anderson
  8. Scott Keeney
(2018)
ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2
eLife 7:e30919.
https://doi.org/10.7554/eLife.30919

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