A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary

Abstract

The chromosomal program of meiotic prophase, comprising events such as laying down of meiotic cohesins, synapsis between homologs, and homologous recombination, must be preceded and enabled by the regulated induction of meiotic prophase genes. This gene regulatory program is poorly understood, particularly in organisms with a segregated germline. We characterized the gene regulatory program of meiotic prophase as it occurs in the mouse fetal ovary. By profiling gene expression in the mouse fetal ovary in mutants with whole tissue and single-cell techniques, we identified 104 genes expressed specifically in pre-meiotic to pachytene germ cells. We characterized the regulation of these genes by 1) retinoic acid (RA), which induces meiosis, 2) Dazl, which is required for germ cell competence to respond to RA, and 3) Stra8, a downstream target of RA required for the chromosomal program of meiotic prophase. Initial induction of practically all identified meiotic prophase genes requires Dazl. In the presence of Dazl, RA induces at least two pathways: one Stra8-independent, and one Stra8-dependent. Genes vary in their induction by Stra8, spanning fully Stra8-independent, partially Stra8-independent, and fully Stra8-dependent. Thus, Stra8 regulates the entirety of the chromosomal program but plays a more nuanced role in governing the gene expression program. We propose that Stra8-independent gene expression enables the stockpiling of selected meiotic structural proteins prior to the commencement of the chromosomal program. Unexpectedly, we discovered that Stra8 is required for prompt down-regulation of itself and Rec8. Germ cells that have expressed and down-regulated Stra8 are refractory to further Stra8 expression. Negative feedback of Stra8, and subsequent resistance to further Stra8 expression, may ensure a single, restricted pulse of Stra8 expression. Collectively, our findings reveal a gene regulatory logic by which germ cells prepare for the chromosomal program of meiotic prophase, and ensure that it is induced only once.

Bone morphogenetic protein and retinoic acid synergistically specify female germ‐cell fate in mice

“…Dotted circles represent samples under the same culture periods. Arrows highlight the differences between the WT and SK cells. Scatter‐plot comparison of gene expression between the WT and SK1 c9 RAB2 cells and the expression of genes reported to be independent (blue), partially dependent (pink), and dependent (red) on Stra8 (Soh et al , ).…”

“…IF analyses revealed that PGCLCs cultured with RA and BMP2 began to express STRA8, a key meiosis inducer (Baltus et al, 2006;Anderson et al, 2008;Dokshin et al, 2013;Soh et al, 2015), as early as c5 [~40.7%/SC (+) cells], and at c7 the vast majority (~91.7%) of SC (+) cells exhibited STRA8 expression, and some of them (~27.1%) were SCP3 (+) ( Fig 2B and C). Remarkably, at c9, more than 90% of SC (+) cells expressed SCP3 with synaptonemal complex-like structure formation, and STRA8 began to wane (Fig 2B and C).…”

“…Consequently, after around E13.5, XY PGCs in the embryonic testes enter into mitotic arrest to differentiate into prospermatogonia (PSG), whereas XX PGCs in the embryonic ovaries progress into meiosis to differentiate into primary oocytes (Spiller & Bowles, ). It has been shown that retinoic acid (RA), apparently synthesized primarily in the mesonephric ducts, induces XX PGCs in embryonic ovaries into the female pathway by up‐regulating the expression of STRA8, a molecule essential for triggering the meiotic prophase, whereas in embryonic testes, RA is degraded by CYP26B1 strongly expressed in nascent Sertoli cells and XY PGCs ensheathed by such cells are induced into the male pathway via an as‐yet‐unknown mechanism (Baltus et al , ; Bowles et al , ; Koubova et al , ; Anderson et al , ; Dokshin et al , ; Soh et al , ).…”

Retinoic acid signaling in regulation of meiosis during embryonic development in mice

“…Soh et al have shown that Stra8 is involved in its own permanent downregulation after induction of meiosis in order to make sure that meiosis is commenced just once in the germ cells (Soh et al, 2015). Soh et al have shown that Stra8 is involved in its own permanent downregulation after induction of meiosis in order to make sure that meiosis is commenced just once in the germ cells (Soh et al, 2015).…”

“…Chromosomal events comprising meiotic cohesin aggregation, synapsis formation, and recombination of homologous chromosomes constitute a chromosomal program.Soh et al have proposed that Stra8-dependent pathways regulate all of chromosomal program while the Stra8-independent pathways bring about stockpiling of specific structural components before the chromosomal program commences(Soh et al, 2015). have shown that under the regulation of RA, CYP51 translocates to the nucleus in the fetal ovarian germ cells thereby promoting meiosis.…”