title: 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.
authors.affiliation: Whitehead Institute, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Y Q Shirleen
authors.initials: YQ
authors.lastname: Soh
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) Utrecht, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Junker
authors.affiliation: Whitehead Institute, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gill
authors.affiliation: Whitehead Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Mueller
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) Utrecht, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
authors.affiliation: Whitehead Institute, Cambridge, Massachusetts, United States of America; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Howard Hughes Medical Institute, Whitehead Institute, Cambridge, Massachusetts, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Page
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D049469:Meiotic Prophase I; D010053:Ovary / Q000166:cytology / Q000196:embryology*; D012756:Sheep / Q000196:embryology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing