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

Abstract

Female fertility requires estrogen to specifically stimulate estrogen receptor α (ERα)-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 ERα in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ERα knockout (UtEpiαERKO) mouse line was generated by crossing Esr mice with Wnt7a-Cre mice. Expression of Wnt7a directed Cre activity generated selective deletion of ERα in uterine epithelium, and female UtEpiαERKO are infertile. Herein, we demonstrate that 17β-estradiol (E 2 )-induced uterine epithelial proliferation was independent of uterine epithelial ERα because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpiαERKO uteri after E 2 treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wildtype (WT) and UtEpiαERKO and mimicked the E 2 stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ERα was necessary to induce lactoferrin, an E 2 -regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ERα did not alter the E 2 -dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpiαERKO 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 ERα in the proliferative response, but ERα is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ERα in uterine tissue and its contribution during pregnancy.conditional knockout | paracrine regulation

Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina

“…Therefore, we infer that epithelial ESR1 is indispensable for keratinocyte commitment and maintenance of epithelial homeostasis by controlling cell differentiation. This is in contrast to the role of epithelial ESR1 in the uterus, where epithelial ESR1 is involved in the maintenance of epithelial cell survival by preventing excessive apoptosis, likely as a result of inactivation of cell cycle progression-related genes (11,27). Subsequently, loss of ESR1 results in enhanced apoptosis in the uterine epithelium (11); such apoptosis was not observed in the vaginal epithelium of K5-Esr1KO mice.…”

“…Classical tissue recombination experiments have suggested that epithelial cell proliferation in female reproductive organs (e.g., uterus, vagina, and mammary gland) is mediated by stromal ESR1 in a paracrine manner (4-6). In contrast, genetic studies in mouse models have shown that epithelial ESR1 is required for cell proliferation in the mammary gland, but not in the uterus (11,12). Therefore, to clarify and extend those observations, we conducted Esr1KO in the mouse vagina and demonstrated that vaginal epithelial cells can proliferate in the absence of epithelial ESR1 in vivo.…”

“…Estrogen-induced growth factors secreted from the stroma subsequently promote epithelial cell proliferation (7)(8)(9)(10). Experiments using epithelial cell-specific KO of Esr1 revealed that estrogen can induce proliferation of uterine epithelial cells despite the absence of epithelial ESR1 (11). In contrast, similar experiments using a mammary epithelium-specific Esr1 KO showed that ESR1 is required in the epithelial cells for mammary gland growth and ductal epithelial cell proliferation (12).…”

“…It is uncertain whether these differences result from different requirements for epithelial ESR1 in the uterus versus the mammary gland or whether they result from methodological differences in tissue recombination experiments (e.g., age of donor, hormone treatment protocol) (13). Irrespective of these differences, there are definite requirements for epithelial ESR1 expression in uterine epithelial functionalization (e.g., lactoferrin gene expression and prevention of cell death in the uterus), as well as in ductal morphogenesis, alveologenesis, and lactation in the mammary gland (11,12).…”

The structure and functions of lactoferrin and its role in human reproduction (a review)

“…Факт отсутствия ЛФ в эндометрии при некото-рых видах бесплодия, а также в эндометрии во время беременности или при приеме больших доз гестаге-нов также свидетельствует о гормональной регуля-ции этого антигена в тканях [49].…”