A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary
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, parti...
| Main Authors: | , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2015
|
| Online Access: | http://hdl.handle.net/1721.1/99763 https://orcid.org/0000-0001-9920-3411 |
| _version_ | 1826214742262284288 |
|---|---|
| author | Junker, Jan Philipp Gill, Mark E. Mueller, Jacob L. van Oudenaarden, Alexander Soh, Ying Qi Shirleen Page, David C |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Junker, Jan Philipp Gill, Mark E. Mueller, Jacob L. van Oudenaarden, Alexander Soh, Ying Qi Shirleen Page, David C |
| author_sort | Junker, Jan Philipp |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:10:45Z |
| format | Article |
| id | mit-1721.1/99763 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:10:45Z |
| publishDate | 2015 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/997632022-10-02T06:50:51Z A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary Junker, Jan Philipp Gill, Mark E. Mueller, Jacob L. van Oudenaarden, Alexander Soh, Ying Qi Shirleen Page, David C Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Physics Whitehead Institute for Biomedical Research Soh, Y. Q. Shirleen Junker, Jan Philipp Gill, Mark E. van Oudenaarden, Alexander Page, David C. 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. Howard Hughes Medical Institute European Research Council (Grant ERC-AdG 294325-GeneNoiseControl) National Institutes of Health (U.S.) (Grant R01-GM068957) Howard Hughes Medical Institute (International Student Research Fellowship) Whitehead Institute for Biomedical Research (Abraham Siegal Fellowship) 2015-11-09T16:45:58Z 2015-11-09T16:45:58Z 2015-09 2015-06 Article http://purl.org/eprint/type/JournalArticle 1553-7404 1553-7390 http://hdl.handle.net/1721.1/99763 Soh, Y. Q. Shirleen, Jan Philipp Junker, Mark E. Gill, Jacob L. Mueller, Alexander van Oudenaarden, and David C. Page. “A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary.” Edited by R. Scott Hawley. PLOS Genetics 11, no. 9 (September 17, 2015): e1005531. https://orcid.org/0000-0001-9920-3411 en_US http://dx.doi.org/10.1371/journal.pgen.1005531 PLOS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Junker, Jan Philipp Gill, Mark E. Mueller, Jacob L. van Oudenaarden, Alexander Soh, Ying Qi Shirleen Page, David C A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary |
| title | A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary |
| title_full | A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary |
| title_fullStr | A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary |
| title_full_unstemmed | A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary |
| title_short | A Gene Regulatory Program for Meiotic Prophase in the Fetal Ovary |
| title_sort | gene regulatory program for meiotic prophase in the fetal ovary |
| url | http://hdl.handle.net/1721.1/99763 https://orcid.org/0000-0001-9920-3411 |
| work_keys_str_mv | AT junkerjanphilipp ageneregulatoryprogramformeioticprophaseinthefetalovary AT gillmarke ageneregulatoryprogramformeioticprophaseinthefetalovary AT muellerjacobl ageneregulatoryprogramformeioticprophaseinthefetalovary AT vanoudenaardenalexander ageneregulatoryprogramformeioticprophaseinthefetalovary AT sohyingqishirleen ageneregulatoryprogramformeioticprophaseinthefetalovary AT pagedavidc ageneregulatoryprogramformeioticprophaseinthefetalovary AT junkerjanphilipp generegulatoryprogramformeioticprophaseinthefetalovary AT gillmarke generegulatoryprogramformeioticprophaseinthefetalovary AT muellerjacobl generegulatoryprogramformeioticprophaseinthefetalovary AT vanoudenaardenalexander generegulatoryprogramformeioticprophaseinthefetalovary AT sohyingqishirleen generegulatoryprogramformeioticprophaseinthefetalovary AT pagedavidc generegulatoryprogramformeioticprophaseinthefetalovary |