Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus

While the function of progesterone receptor (PR) has been studied in the mouse vagina and uterus, its regulation and function in the cervix has not been described. We selectively deleted epithelial PR in the female reproductive tracts using the Cre/LoxP recombination system. We found that epithelial PR was required for induction of apoptosis and suppression of cell proliferation by progesterone (P4) in the cervical and vaginal epithelium. We also found that epithelial PR was dispensable for P4 to suppress apoptosis and proliferation in the uterine epithelium. PR is encoded by the Pgr gene, which is regulated by estrogen receptor ? (ER?) in the female reproductive tracts. Using knock?in mouse models expressing ER? mutants, we determined that the DNA?binding domain (DBD) and AF2 domain of ER? were required for upregulation of Pgr in the cervix and vagina as well as the uterine stroma. The ER? AF1 domain was required for upregulation of Pgr in the vaginal stroma and epithelium and cervical epithelium, but not in the uterine and cervical stroma. ER? DBD, AF1, and AF2 were required for suppression of Pgr in the uterine epithelium, which was mediated by stromal ER?. Epithelial ER? was responsible for upregulation of epithelial Pgr in the cervix and vagina. Our results indicate that regulation and functions of epithelial PR are different in the cervix, vagina, and uterus.