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

Abstract
Data availability
Article and author information
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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

The following data sets were generated

1. Jain D
2. Puno R
3. Meydan C
4. Lailler N
5. Mason CE
6. Lima CD
7. Anderson KV
8. Keeney S
(2017) ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE108044).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE108044

The following previously published data sets were used

1. Hsu PJ
2. Zhu Y
3. Ma H
4. Cui Y
5. Shi X
6. Lu Z
7. Shi H
8. Luo G
9. Dai Q
10. Shen B
11. He C
(2017) YTHDC2 regulates spermatogenesis through promoting the translation of N6-methyladenosine-modified RNA
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE98085).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE98085
1. Soumillon M
2. Necsulea A
3. Weier M
4. Brawand D
5. Zhang X
6. Gu H
7. Barthès P
8. Kokkinaki M
9. Nef S
10. Gnirke A
11. Dym M
12. de Massy B
13. Mikkelsen TS
14. Kaessmann H
(2013) 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).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE43717

Article and author information

Author details

Devanshi Jain

Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
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.
Cem Meydan

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Nathalie Lailler

Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.

"This ORCID iD identifies the author of this article:" 0000-0002-9163-6092
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.
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.

"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.

Copyright

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.