Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses
Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses
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DOI：
10.1073/pnas.1013226107
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发表时间：
2010-11-09
影响因子：
11.1
通讯作者：
Korach, Kenneth S.
中科院分区：
文献类型：
--
作者：
Winuthayanon, Wipawee;Hewitt, Sylvia C.;Korach, Kenneth S.
雌性生育需要雌激素来特异性地刺激成年小鼠子宫上皮细胞依赖雌激素受体(ERα)的生长，而未成熟的雌性小鼠在间质和上皮中都表现出增殖。为了探讨ERα在子宫上皮与基质中介导雌激素作用的相对作用，通过将ESR小鼠与Wnt7a-CRE小鼠杂交，建立了子宫上皮特异性ERα基因敲除(UtEpiαErko)小鼠系。Wnt7a的表达导致子宫上皮中ERα选择性缺失，而雌性UtEpiαErko是不育的。在这里，我们证明了17β-雌二醇(E-2)诱导的子宫上皮细胞增殖不依赖于子宫上皮ERα，因为E-2处理后子宫上皮细胞DNA合成和有丝分裂介质的上调持续存在。IGF-1处理导致野生型(WT)和UtEpiαErko的ER激活不依赖配体，并模拟E-2对子宫上皮DNA合成的刺激作用。子宫上皮ERα是诱导乳铁蛋白所必需的，乳铁蛋白是一种受E-2调节的分泌性蛋白，选择性地在子宫上皮中合成。然而，子宫上皮ERα的缺失并不改变上皮中孕酮受体(PR)的下调。值得注意的是，在E-2处理3d后，UtEpi Alpha Erko的子宫上皮有强烈的细胞凋亡证据。因此，我们推测雌激素诱导的子宫增生症涉及子宫上皮ERα在增殖反应中的可有可无的作用，但在增殖后需要ERα来防止子宫上皮细胞的凋亡，以确保完整的子宫上皮反应，这说明了ERα在子宫组织中的不同细胞作用及其在妊娠期间的作用。
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 (E-2)-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 E-2 treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wildtype (WT) and UtEpi alpha ERKO and mimicked the E-2 stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ER alpha was necessary to induce lactoferrin, an E-2-regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ER alpha did not alter the E-2-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 E-2 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.