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

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.

A SARS-CoV-2 – host proximity interactome

“…4a, blue). IBTK (a protein found in immunoprecipitates of the translation initiation factor eIF4A 13,45,46 ), MEOIC (a partner of the only RNA helicase-containing m6A reader, YTHDC2 47 ) and ANGEL1 (a binding partner of the mRNA cap binding protein eIF4E 48 ) were found in proximity to NSP16, a methyltransferase that mediates 2'-O-ribose methylation of the viral mRNA 5'-cap structure. As expected, the nucleocapsid protein, N, also established multiple proximity interactions with RNA binding proteins (a subset is shown in Fig.…”

The RNA-binding protein Igf2bp3 is critical for embryonic and germline development in zebrafish

“…The mechanism that Igf2bp3 acts through to regulate the germline remains unknown. However, many proteins associated with m6A modifications, known as m6A readers, have been shown to be important for fertility and germline development, such as Ythdf2 (Zhao et al, 2017), Ythdc2 (Hsu et al, 2017;Soh et al, 2017;Jain et al, 2018) and a closely related Drosophila homolog, Bcgn (Gateff, 1982). Igf2bp proteins were found to be associated with m6A modifications (Huang et al, 2018).…”

Genome-wide association study in European patients with congenital heart disease identifies risk loci for transposition of the great arteries and anomalies of the thoracic arteries and veins and expression of discovered candidate genes in the developing heart

“…The same SNP was also strongly associated with CHD risk in general, with YTHDC2, an RNA helicase involved in meiosis as the closest gene. 49 The second SNP for septal defects is related to ASIC2, whose loss leads to hypertension in null mice. 50 Restricting the patient cohort to ASD, we confirmed SNP rs870142, which we had previously identified.…”