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

Devanshi Jain,Cem Meydan,Kathryn V Anderson,Nathalie Lailler,M Rhyan Puno,Scott Keeney,Christopher E Mason,Christopher D Lima

doi:10.7554/elife.30919

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.

Highlights

Sexual reproduction requires formation of gametes with half the genome complement of the parent organism
SYCP3-positive axial elements begin to form during the leptotene stage of meiotic prophase I; these elongate and begin to align with homologous chromosome axes to form the tripartite synaptonemal complex in the zygotene stage; the synaptonemal complex connects homologous chromosomes along their lengths in the pachytene stage; and the synaptonemal complex begins to disassemble during the diplotene stage (Figure 1B)
This study establishes an essential function for Ythdc2 in the germlines of male and female mice, at the stage when stem cells transition from mitotic to meiotic divisions

Summary

Introduction

Sexual reproduction requires formation of gametes with half the genome complement of the parent organism. The specialized cell division of meiosis achieves this genome reduction by appending two rounds of chromosome segregation to one round of DNA replication (Page and Hawley, 2003). Prior to the first division, homologous chromosomes pair and recombine to form temporary connections that stabilize the chromosomes on the metaphase I spindle (Page and Hawley, 2003; Hunter, 2007). Errors in these processes can cause gametogenic failure and infertility, or yield aneuploid gametes that in turn lead to miscarriage or birth defects in offspring (Hassold and Hunt, 2001; Sasaki et al, 2010). Bgcn lacks a YTH domain and a clear match to the YTHDMCa2rkkDera

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Conclusion