Meioc maintains an extended meiotic prophase I in mice

Abstract

The meiosis-specific chromosomal events of homolog pairing, synapsis, and recombination occur over an extended meiotic prophase I that is many times longer than prophase of mitosis. Here we show that, in mice, maintenance of an extended meiotic prophase I requires the gene Meioc, a germ-cell specific factor conserved in most metazoans. In mice, Meioc is expressed in male and female germ cells upon initiation of and throughout meiotic prophase I. Mouse germ cells lacking Meioc initiate meiosis: they undergo pre-meiotic DNA replication, they express proteins involved in synapsis and recombination, and a subset of cells progress as far as the zygotene stage of prophase I. However, cells in early meiotic prophase—as early as the preleptotene stage—proceed to condense their chromosomes and assemble a spindle, as if having progressed to metaphase. Meioc-deficient spermatocytes that have initiated synapsis mis-express CYCLIN A2, which is normally expressed in mitotic spermatogonia, suggesting a failure to properly transition to a meiotic cell cycle program. MEIOC interacts with YTHDC2, and the two proteins pull-down an overlapping set of mitosis-associated transcripts. We conclude that when the meiotic chromosomal program is initiated, Meioc is simultaneously induced so as to extend meiotic prophase. Specifically, MEIOC, together with YTHDC2, promotes a meiotic (as opposed to mitotic) cell cycle program via post-transcriptional control of their target transcripts.

Staged developmental mapping and X chromosome transcriptional dynamics during mouse spermatogenesis

“…The mitotic expansion of spermatogonia produces large numbers of spermatocytes, which then undergo male meiosis where two consecutive cell divisions give rise to four haploid spermatids. In contrast to mitotic cell divisions, prophase of meiosis I is extremely prolonged, lasting up to 10 days in male mice (Soh et al, 2017). This process has been histologically described, but a full transcriptional characterization of spermatocytes 305 undergoing meiosis is lacking.…”

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

“…Importantly, however, BrdU + SYCP3 + double-positive cells were observed in the mutant at a frequency comparable to the controls (Figure 5C, p = 0.03 comparing percent of SYCP3 + cells in wild type/heterozygous and mutant and p = 0.53 comparing percent of double-positive cells (t-test)). The presence of these presumptive preleptotene spermatocytes suggests that pre-meiotic DNA replication occurs in a timely manner in the Ythdc2 ketu/ketu mutant, similar to Meioc -/- (Abby et al, 2016;Soh et al, 2017), although modest defects in timing or efficiency cannot be ruled out.…”

“…In normal spermatogenesis, cyclin A2 (CCNA2) is expressed during mitotic cell cycles in spermatogonia, but is downregulated at or before meiotic entry and is undetectable in SYCP3-positive spermatocytes (Ravnik and Wolgemuth, 1999). Meioc -/spermatocytes fail to properly extinguish CCNA2 expression, suggesting that inappropriate retention of the spermatogonial (mitotic) cell cycle machinery contributes to precocious metaphase and other meiotic defects (Soh et al, 2017). When testis sections from 12-, 14-, and 15-dpp wild-type animals were immunostained for SYCP3 and CCNA2, the expected mutually exclusive localization pattern was observed: CCNA2 + spermatogonia were located at tubule peripheries while SYCP3 + spermatocytes occupied more lumenal positions (Figure 5D, .…”

“…The closest homolog in Drosophila melanogaster is Bgcn (benign gonial cell neoplasm), which regulates germ cell differentiation via translational control of target mRNAs (Li et al, 2009b;Kim et al, 2010;Insco et al, 2012;Chen et al, 2014). Bgcn was thus proposed to be the fruit fly ortholog of YTHDC2 (Soh et al, 2017). However, Bgcn lacks a YTH domain and a clear match to the R3H domain (Figure 10A) and is altered in motifs critical for ATP binding and hydrolysis (Ohlstein et al, 2000) ( Figure Figure 8.…”

“…In D. melanogaster, the product of the bag of marbles (bam) gene is a functional collaborator and direct binding partner of Bgcn (Gonczy et al, 1997;Lavoie et al, 1999;Ohlstein et al, 2000;Li et al, 2009b;Shen et al, 2009;Kim et al, 2010;Insco et al, 2012;Chen et al, 2014). By analogy with YTHDC2-MEIOC, it was thus proposed that Bam may be a functional analog of MEIOC (Soh et al, 2017). However, no sequence similarity between MEIOC and Bam has been detected.…”