Dubois Sharon L, Acosta-Martínez Maricedes, DeJoseph Mary R, Wolfe Andrew, Radovick Sally, Boehm Ulrich, Urban Janice H, Levine Jon E
Neuroscience Training Program (S.L.D.), Department of Neuroscience (S.L.D., J.E.L.), University of Wisconsin-Madison, Madison, Wisconsin 53715; Department of Physiology and Biophysics (M.A.-M.), Stony Brook University, Stony Brook, New York 11794; Department of Physiology and Biophysics (M.R.D., J.H.U.), Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064; Department of Pediatrics (A.W., S.R.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Pharmacology and Toxicology (U.B.), University of Saarland School of Medicine, Homburg, Germany D-66421; and Wisconsin National Primate Research Center (J.E.L.), Madison, Wisconsin 53715.
Endocrinology. 2015 Mar;156(3):1111-20. doi: 10.1210/en.2014-1851. Epub 2014 Dec 29.
Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor α (ERα) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E2) activation of ERα in kisspeptin neurons in the arcuate nucleus (ARC) suppresses GnRH/LH secretion (negative feedback), whereas E2 activation of ERα in kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) mediates the release of preovulatory GnRH/LH surges (positive feedback). To test these hypotheses, we generated mice bearing kisspeptin cell-specific deletion of ERα (KERαKO) and treated them with E2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E2 effectively suppressed LH levels in ovariectomized (OVX) wild-type (WT) mice to the levels seen in ovary-intact mice. Surprisingly, however, despite the fact that E2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KERαKO mice, E2 also effectively decreased LH levels in OVX KERαKO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E2 stimulated LH surges in WT mice, but had no effect in KERαKO mice. These experiments clearly demonstrate that ERα in kisspeptin neurons is required for the positive, but not negative feedback actions of E2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KERαKO mice to exhibit GnRH/LH surges reflects the role of ERα in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.
下丘脑的 kisspeptin（Kiss1）神经元表达雌激素受体α（ERα），并对雌性啮齿动物的促性腺激素释放激素（GnRH）/促黄体生成素（LH）分泌发挥调控作用。有观点认为，弓状核（ARC）中 kisspeptin 神经元的 ERα 被雌二醇（E2）激活会抑制 GnRH/LH 分泌（负反馈），而腹内侧视前核（AVPV）中 kisspeptin 神经元的 ERα 被 E2 激活则介导排卵前 GnRH/LH 峰的释放（正反馈）。为验证这些假说，我们构建了 kisspeptin 细胞特异性缺失 ERα 的小鼠（KERαKO），并用能对 GnRH/LH 分泌产生负反馈或正反馈作用的 E2 方案对其进行处理。采用负反馈方案时，正如预期的那样，E2 有效地将去卵巢（OVX）野生型（WT）小鼠的 LH 水平抑制到卵巢完整小鼠的水平。然而，令人惊讶的是，尽管在 KERαKO 小鼠的 ARC 和 AVPV 中 E2 对 Kiss1 mRNA 表达的调控作用均被消除，但 E2 仍能有效地将 OVX KERαKO 小鼠的 LH 水平降低到卵巢完整小鼠的水平。相反，采用正反馈方案时，E2 刺激 WT 小鼠出现 LH 峰，但对 KERαKO 小鼠没有影响。这些实验清楚地表明，成年雌性小鼠中，kisspeptin 神经元中的 ERα 是 E2 对 GnRH/LH 分泌产生正反馈而非负反馈作用所必需的。KERαKO 小鼠未能出现 GnRH/LH 峰是反映 ERα 在 kisspeptin 神经元发育中的作用、在导致 GnRH/LH 峰释放的活跃信号传导过程中的作用，还是两者兼而有之，仍有待确定。
