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PMID: 29360036 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

eLife ·Vol. 7 ·2018-00-23

Jain D, Puno MR, Meydan C, Lailler N, Mason CE, Lima CD, Anderson KV, Keeney S

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.

Keywords
Bam Bgcn D. melanogaster MEIOC chromosomes evolutionary biology gametogenesis genes genomics m6A meiosis mouse
MeSH Terms
Animals Cell Cycle Proteins/genetics,metabolism Gene Expression Regulation Genetic Testing Germ Cells/physiology Infertility Male Meiosis Mice Mutation, Missense RNA Helicases/genetics,metabolism
Chemicals
Cell Cycle Proteins MEIOC protein, mouse RNA Helicases Ythdc2 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Jain Devanshi ORCID
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
Puno M Rhyan
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States. | Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
Meydan Cem
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States. | The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States.
Lailler Nathalie
Integrated Genomics Operation, Memorial Sloan Kettering Cancer Center, New York, United States.
Mason Christopher E
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States. | The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, United States. | The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, United States.
Lima Christopher D ORCID
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States. | Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
Anderson Kathryn V
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
Keeney Scott ORCID
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States. | Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
Conflict of Interest

DJ, MP, CM, NL, CM, CL, KA, SK No competing interests declared

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Article Info
Journal
eLife
Abbr.
Elife
ISSN
2050-084X
DOI
10.7554/eLife.30919
Published
2018-00-23
Epub
2018-00-23
Language
English
Region
England
NLM ID
101579614
PMCID
PMC5832417
Grants
NASA · NNX14AH50G 15-15Omni2-0063 · United States
Bill and Melinda Gates Foundation · OPP1151054 · International
Howard Hughes Medical Institute · United States
NCI NIH HHS · P30 CA008748 · United States
NICHD NIH HHS · R37 HD035455 · United States
NIGMS NIH HHS · R35 GM118080 · United States
External Links
PubMed source DOI: 10.7554/eLife.30919 PMC Full Text View journal details
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