Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function

Area of Science:

• Reproductive biology
• Endocrinology
• Molecular genetics

Background:

• Progesterone receptor (PR) is critical for endometrial function, mediating progesterone's effects.
• Previous studies using ex vivo models suggested stromal PR is important, but the role of epithelial PR remained unclear.

Purpose of the Study:

• To define the in vivo role of PR specifically in the uterine epithelium.
• To investigate whether PR directly regulates epithelial gene transcription in the uterus.

Main Methods:

• Utilized a mouse model (Wnt7a-Cre(+)PR(f/-)) with conditional knockout of PR in uterine epithelial cells.
• Analyzed progesterone target gene expression (e.g., Ihh) in knockout mice.
• Performed ChIP-on-chip analysis to identify PR binding sites.
• Conducted cotransfection assays to confirm direct transcriptional regulation.

Main Results:

• PR knockout in uterine epithelium prevented progesterone-induced expression of target genes like Ihh.
• PR was shown to directly bind to and regulate the Ihh promoter.
• Female knockout mice exhibited infertility, characterized by impaired embryo attachment, decidualization defects, and uncontrolled epithelial cell proliferation.
• Progesterone failed to inhibit neonatal endometrial glandular development in knockout mice.

Conclusions:

• Epithelial PR is indispensable for mediating progesterone's effects on uterine epithelial gene expression.
• Epithelial PR plays a critical role in regulating uterine function, including fertility and endometrial development.
• These findings highlight a direct transcriptional role for PR in the uterine epithelium, essential for reproductive success.