Abstract
The germ line provides the cellular link between generations of multicellular organisms, its cells entering the meiotic cell cycle only once each generation. However, the mechanisms governing this initiation of meiosis remain poorly understood. Here, we examined cells undergoing meiotic initiation in mice, and we found that initiation involves the dramatic upregulation of a transcriptional network of thousands of genes whose expression is not limited to meiosis. This broad gene expression program is directly upregulated by STRA8, encoded by a germ cell-specific gene required for meiotic initiation. STRA8 binds its own promoter and those of thousands of other genes, including meiotic prophase genes, factors mediating DNA replication and the G1-S cell-cycle transition, and genes that promote the lengthy prophase unique to meiosis I. We conclude that, in mice, the robust amplification of this extraordinarily broad transcription program by a common factor triggers initiation of meiosis.
Highlights
A key feature of sexual reproduction is meiosis, a specialized cell cycle in which one round of DNA replication precedes two rounds of chromosome segregation to produce haploid gametes
By chemically modulating the levels of retinoic acid, which is required for spermatogonial differentiation (Endo et al, 2015; van Pelt and de Rooij, 1990), we can induce synchronous progression of germ cells through spermatogenesis and collect testes enriched for preleptotene cells (Figure 1A) (Hogarth et al, 2013; Romer et al, 2018)
We demonstrate that STRA8, a transcriptional activator, triggers the unique meiotic cell cycle by amplifying the expression of meiotic prophase I genes, G1-S cell-cycle genes, and factors that inhibit the mitotic program
Summary
A key feature of sexual reproduction is meiosis, a specialized cell cycle in which one round of DNA replication precedes two rounds of chromosome segregation to produce haploid gametes. Stra8-deficient cells do not robustly express meiotic factors, or progress to the leptotene stage and begin the chromosomal events of meiosis (Anderson et al, 2008; Baltus et al, 2006; Soh et al, 2015). These genetic studies of Stra deficiency suggest that the decision to initiate meiosis occurs in the middle of the preleptotene stage, upstream of meiotic S phase. We suggest that the robust amplification of such genes, together with factors that maintain the meiosis-specific extended prophase, triggers the one meiotic cell cycle in each generation
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