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

Authors

Kirsten M Smith
Doan T Dinh
Lisa K Akison
Matilda Nicholls
Kylie R Dunning
Atsushi Morimoto
John P Lydon
Darryl L Russell
Rebecca L Robker

Publication Date

5-5-2022

Journal

Cells

DOI

10.3390/cells11091563

PMID

35563869

PMCID

PMC9105733

PubMedCentral® Posted Date

5-5-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Female, Granulosa Cells, Mammals, Mice, Mice, Knockout, Ovulation, Progesterone, Protein Isoforms, Receptors, Progesterone, progesterone receptor, PGR-A, PGR-B, PRKO, transcriptome, ovulation, ovarian stroma, granulosa cells, pathways analysis, respiration

Abstract

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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