Nonclassical estrogen receptor α signaling mediates negative feedback in the female mouse reproductive axis
Nonclassical estrogen receptor α signaling mediates negative feedback in the female mouse reproductive axis
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DOI：
10.1073/pnas.0611514104
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发表时间：
2007-05-08
影响因子：
11.1
通讯作者：
Jameson, J. L.
中科院分区：
文献类型：
--
作者：
Glidewell-Kenney, C.;Hurley, L. A.;Jameson, J. L.
卵巢雌激素在排卵周期期间对黄体生成素 (LH) 分泌发挥正反馈和负反馈控制。雌激素受体（ER）a而非ERP敲除小鼠缺乏雌激素反馈。因此，雌激素反馈似乎主要由 ER α 介导。然而，现在人们认识到，除了与 DNA 中的雌激素反应元件 (ERE) 结合以改变靶基因转录外，ERa 还通过不依赖于 ERE 的或非经典途径发出信号，以及这些途径在传递雌激素反馈中的相对贡献仍然未知。此前，我们创建了表达 ERa (AA) 突变形式的敲入小鼠模型，其 ERE 依赖性活性被消除，但 ERE 独立活性完整。将此等位基因培育到 ER α 缺失 (-/-) 背景上，我们检查了不依赖于 ERE 的 ER α 信号通路在体内传递女性下丘脑-垂体轴的雌激素反馈调节的能力。与ER α(-/-) 小鼠相比，ER α(-/AA) 小鼠的血清LH 水平降低69.9%。此外，与野生型一样，ERa-/AA 小鼠在卵巢切除 (OVX) 后表现出 LH 升高。此外，OVX ER α(-/AA) 小鼠中雌激素治疗显着抑制了 OVX 后血清 LH 的升高。然而，与野生型不同，ER α(-/AA) 和 ER α(-/-) 小鼠均未能表现出动情周期、自发排卵或下午 LH 激增对雌激素的反应。这些结果表明，不依赖于 ERE 的 ER α 信号传导足以传达雌激素负反馈作用的主要部分，而正反馈和自发排卵周期则需要依赖于 ERE 的 ER α 信号传导。
Ovarian estrogen exerts both positive and negative feedback control over luteinizing hormone (LH) secretion during the ovulatory cycle. Estrogen receptor (ER) a but not ERP knockout mice lack estrogen feedback. Thus, estrogen feedback appears to be primarily mediated by ER alpha. However, it is now recognized that, in addition to binding to estrogen response elements (EREs) in DNA to alter target gene transcription, ERa signals through ERE-independent or nonclassical pathways, and the relative contributions of these pathways in conveying estrogen feedback remain unknown. Previously we created a knockin mouse model expressing a mutant form of ERa (AA) with ablated ERE-dependent but intact ERE-independent activity. Breeding this allele onto the ER alpha-null (-/-) background, we examine the ability of ERE-independent ER alpha signaling pathways to convey estrogen feedback regulation of the female hypothalamic-pituitary axis in vivo. ER alpha(-/AA) exhibited 69.9% lower serum LH levels compared with ER alpha(-/-) mice. Additionally, like wild type, ERa-/AA mice exhibited elevated LH after ovariectomy (OVX). Furthermore, the post-OVX rise in serum LH was significantly suppressed by estrogen treatment in OVX ER alpha(-/AA) mice. However, unlike wild type, both ER alpha(-/AA) and ER alpha(-/-) mice failed to exhibit estrous cyclicity, spontaneous ovulation, or an afternoon LH surge response to estrogen. These results indicate that ERE-independent ER alpha signaling is sufficient to convey a major portion of estrogen's negative feedback actions, whereas positive feedback and spontaneous ovulatory cyclicity require ERE-dependent ER alpha signaling.