Uterine epithelial estrogen receptor ? is dispensable for proliferation but essential for complete biological and biochemical responses.

ABSTRACT: Female fertility requires estrogen to specifically stimulate estrogen receptor ? (ER?)-dependent growth of the uterine epithelium in adult mice, while immature females show proliferation in both stroma and epithelium. To address the relative roles of ER? in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ER? knockout (UtEpi?ERKO) mouse line was generated by crossing Esr mice with Wnt7a-Cre mice. Expression of Wnt7a directed Cre activity generated selective deletion of ER? in uterine epithelium, and female UtEpi?ERKO are infertile. Herein, we demonstrate that 17?-estradiol (E(2))-induced uterine epithelial proliferation was independent of uterine epithelial ER? because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpi?ERKO uteri after E(2) treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wild-type (WT) and UtEpi?ERKO and mimicked the E(2) stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ER? was necessary to induce lactoferrin, an E(2)-regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ER? did not alter the E(2)-dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpi?ERKO had robust evidence of apoptosis after 3 d of E(2) treatment. Therefore, we surmise that estrogen induced uterine hyperplasia involves a dispensable role for uterine epithelial ER? in the proliferative response, but ER? is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ER? in uterine tissue and its contribution during pregnancy.

SUBMITTER: Winuthayanon W 

PROVIDER: S-EPMC2984169 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature