Uterine Epithelial Progesterone Receptor Governs Uterine Receptivity through Epithelial Cell Differentiation

Mona Gebril, Yasushi Hirota, Shizu Aikawa, Yamato Fukui, Tetsuaki Kaku, Mitsunori Matsuo, Tomoyuki Hirata, Shun Akaeda, Takehiro Hiraoka, Ryoko Shimizu-Hirota, Norihiko Takeda, Tamer Taha, Osama Al Balah, Mohamed Amr H. Elnoury, Tomoyuki Fujii, Yutaka Osuga

Research output: Contribution to journalArticlepeer-review

Abstract

Progesterone receptor (PGR) is indispensable for pregnancy in mammals. Uterine PGR responds to the heightened levels of ovarian progesterone (P4) after ovulation and regulates uterine gene transcription for successful embryo implantation. Although epithelial and stromal P4-PGR signaling may interact with each other to form appropriate endometrial milieu for uterine receptivity and the subsequent embryo attachment, it remains unclear what the specific roles of epithelial P4-PGR signaling in the adult uterus are. Here we generated mice with epithelial deletion of Pgr in the adult uterus (Pgrfl/flLtfCre/+ mice) by crossing Pgr-floxed and Ltf-Cre mice. Pgrfl/flLtfCre/+ mice are infertile due to the impairment of embryo attachment. Pgrfl/flLtfCre/+ uteri did not exhibit epithelial growth arrest, suggesting compromised uterine receptivity. Both epithelial and stromal expressions of P4-responsive genes decreased in Pgrfl/flLtfCre/+ mice during the peri-implantation period, indicating that epithelial Pgr deletion affects not only epithelial but stromal P4 responsiveness. In addition, uterine LIF, an inducer of embryo attachment, was decreased in Pgrfl/flLtfCre/+ mice. The RNA-seq analysis using luminal epithelial specimens dissected out by laser capture microdissection revealed that the signaling pathways related to extracellular matrix, cell adhesion, and cell proliferation are altered in Pgr fl/flLtf Cre/+ mice. These findings suggest that epithelial PGR controls both epithelial and stromal P4 responsiveness and epithelial cell differentiation, which provides normal uterine receptivity and subsequent embryo attachment.

Original languageEnglish
Article numberbqaa195
JournalEndocrinology (United States)
Volume161
Issue number12
DOIs
Publication statusPublished - 2020 Dec 1

Keywords

  • cell proliferation
  • luminal epithelium
  • progesterone
  • progesterone receptor
  • stroma
  • uterus

ASJC Scopus subject areas

  • Endocrinology

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