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
-
ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE108044).
-
YTHDC2 regulates spermatogenesis through promoting the translation of N6-methyladenosine-modified RNAPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE98085).
-
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.
Metrics
-
- 3,594
- views
-
- 630
- downloads
-
- 136
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2
eLife 7:e30919.
https://doi.org/10.7554/eLife.30919
Further reading
-
- Chromosomes and Gene Expression
- Neuroscience
Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell-type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.
-
- Biochemistry and Chemical Biology
- Chromosomes and Gene Expression
The mRNA 5'-cap structure removal by the decapping enzyme DCP2 is a critical step in gene regulation. While DCP2 is the catalytic subunit in the decapping complex, its activity is strongly enhanced by multiple factors, particularly DCP1, which is the major activator in yeast. However, the precise role of DCP1 in metazoans has yet to be fully elucidated. Moreover, in humans, the specific biological functions of the two DCP1 paralogs, DCP1a and DCP1b, remain largely unknown. To investigate the role of human DCP1, we generated cell lines that were deficient in DCP1a, DCP1b, or both to evaluate the importance of DCP1 in the decapping machinery. Our results highlight the importance of human DCP1 in decapping process and show that the EVH1 domain of DCP1 enhances the mRNA-binding affinity of DCP2. Transcriptome and metabolome analyses outline the distinct functions of DCP1a and DCP1b in human cells, regulating specific endogenous mRNA targets and biological processes. Overall, our findings provide insights into the molecular mechanism of human DCP1 in mRNA decapping and shed light on the distinct functions of its paralogs.
