期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：45
页码：19272-19277
DOI：10.1073/pnas.1013226107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Female fertility requires estrogen to specifically stimulate estrogen receptor {alpha} (ER{alpha})-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{alpha} in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ER{alpha} knockout (UtEpi{alpha}ERKO) mouse line was generated by crossing Esr mice with Wnt7a-Cre mice. Expression of Wnt7a directed Cre activity generated selective deletion of ER{alpha} in uterine epithelium, and female UtEpi{alpha}ERKO are infertile. Herein, we demonstrate that 17{beta}-estradiol (E2)-induced uterine epithelial proliferation was independent of uterine epithelial ER{alpha} because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpi{alpha}ERKO uteri after E2 treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wild-type (WT) and UtEpi{alpha}ERKO and mimicked the E2 stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ER{alpha} was necessary to induce lactoferrin, an E2-regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ER{alpha} did not alter the E2-dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpi{alpha}ERKO had robust evidence of apoptosis after 3 d of E2 treatment. Therefore, we surmise that estrogen induced uterine hyperplasia involves a dispensable role for uterine epithelial ER{alpha} in the proliferative response, but ER{alpha} is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ER{alpha} in uterine tissue and its contribution during pregnancy.
