A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary

<div><p>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) <i>Dazl</i>, which is required for germ cell competence to respond to RA, and 3) <i>Stra8</i>, a downstream target of RA required for the chromosomal program of meiotic prophase. Initial induction of practically all identified meiotic prophase genes requires <i>Dazl</i>. In the presence of <i>Dazl</i>, RA induces at least two pathways: one <i>Stra8</i>-independent, and one <i>Stra8</i>-dependent. Genes vary in their induction by <i>Stra8</i>, spanning fully <i>Stra8</i>-independent, partially <i>Stra8</i>-independent, and fully <i>Stra8</i>-dependent. Thus, <i>Stra8</i> regulates the entirety of the chromosomal program but plays a more nuanced role in governing the gene expression program. We propose that <i>Stra8</i>-independent gene expression enables the stockpiling of selected meiotic structural proteins prior to the commencement of the chromosomal program. Unexpectedly, we discovered that <i>Stra8</i> is required for prompt down-regulation of itself and <i>Rec8</i>. Germ cells that have expressed and down-regulated <i>Stra8</i> are refractory to further <i>Stra8</i> expression. Negative feedback of <i>Stra8</i>, and subsequent resistance to further <i>Stra8</i> expression, may ensure a single, restricted pulse of <i>Stra8</i> 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.</p>