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Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation

Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of...

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Autores principales: Smith, Kirsten M., Dinh, Doan T., Akison, Lisa K., Nicholls, Matilda, Dunning, Kylie R., Morimoto, Atsushi, Lydon, John P., Russell, Darryl L., Robker, Rebecca L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105733/
https://www.ncbi.nlm.nih.gov/pubmed/35563869
http://dx.doi.org/10.3390/cells11091563
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author Smith, Kirsten M.
Dinh, Doan T.
Akison, Lisa K.
Nicholls, Matilda
Dunning, Kylie R.
Morimoto, Atsushi
Lydon, John P.
Russell, Darryl L.
Robker, Rebecca L.
author_facet Smith, Kirsten M.
Dinh, Doan T.
Akison, Lisa K.
Nicholls, Matilda
Dunning, Kylie R.
Morimoto, Atsushi
Lydon, John P.
Russell, Darryl L.
Robker, Rebecca L.
author_sort Smith, Kirsten M.
collection PubMed
description Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of the PGR within each cellular compartment of the ovary, using mice null for the PGR (PRKO), as well as isoform-specific null mice. The PGR was expressed in ovarian granulosa and stromal cells and although PRKO ovaries showed no visible histological changes in preovulatory ovarian morphology, follicle rupture did not occur. Reciprocal ovarian transplant experiments established the necessity of ovarian PGR expression for ovulation. Cumulus–oocyte complexes of PRKO mice exhibited normal morphology but showed some altered gene expression. The examination of mitochondrial activity showed subtle differences in PRKO oocytes but no differences in granulosa cell respiration, glycolysis or β-oxidation. Concurrently, RNA-seq identified novel functional pathways through which the PGR may regulate ovulation. PGR-A was the predominant transcriptionally active isoform in granulosa cells and 154 key PGR-dependent genes were identified, including a secondary network of transcription factors. In addition, the PGR regulated unique gene networks in the ovarian stroma. Collectively, we establish the effector pathways activated by the PGR across the ovarian cell types and conclude that PGR coordinates gene expression in the cumulus, granulosa and stromal cells at ovulation. Identifying these networks linking the PGR to ovulation provides novel targets for fertility therapeutics and nonhormonal contraceptive development.
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spelling pubmed-91057332022-05-14 Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation Smith, Kirsten M. Dinh, Doan T. Akison, Lisa K. Nicholls, Matilda Dunning, Kylie R. Morimoto, Atsushi Lydon, John P. Russell, Darryl L. Robker, Rebecca L. Cells Article Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of the PGR within each cellular compartment of the ovary, using mice null for the PGR (PRKO), as well as isoform-specific null mice. The PGR was expressed in ovarian granulosa and stromal cells and although PRKO ovaries showed no visible histological changes in preovulatory ovarian morphology, follicle rupture did not occur. Reciprocal ovarian transplant experiments established the necessity of ovarian PGR expression for ovulation. Cumulus–oocyte complexes of PRKO mice exhibited normal morphology but showed some altered gene expression. The examination of mitochondrial activity showed subtle differences in PRKO oocytes but no differences in granulosa cell respiration, glycolysis or β-oxidation. Concurrently, RNA-seq identified novel functional pathways through which the PGR may regulate ovulation. PGR-A was the predominant transcriptionally active isoform in granulosa cells and 154 key PGR-dependent genes were identified, including a secondary network of transcription factors. In addition, the PGR regulated unique gene networks in the ovarian stroma. Collectively, we establish the effector pathways activated by the PGR across the ovarian cell types and conclude that PGR coordinates gene expression in the cumulus, granulosa and stromal cells at ovulation. Identifying these networks linking the PGR to ovulation provides novel targets for fertility therapeutics and nonhormonal contraceptive development. MDPI 2022-05-05 /pmc/articles/PMC9105733/ /pubmed/35563869 http://dx.doi.org/10.3390/cells11091563 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Smith, Kirsten M.
Dinh, Doan T.
Akison, Lisa K.
Nicholls, Matilda
Dunning, Kylie R.
Morimoto, Atsushi
Lydon, John P.
Russell, Darryl L.
Robker, Rebecca L.
Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation
title Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation
title_full Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation
title_fullStr Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation
title_full_unstemmed Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation
title_short Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation
title_sort intraovarian, isoform-specific transcriptional roles of progesterone receptor in ovulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105733/
https://www.ncbi.nlm.nih.gov/pubmed/35563869
http://dx.doi.org/10.3390/cells11091563
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