Positive, But Not Negative Feedback Actions of Estradiol in Adult Female Mice Require Estrogen Receptor α in Kisspeptin Neurons
Positive, But Not Negative Feedback Actions of Estradiol in Adult Female Mice Require Estrogen Receptor α in Kisspeptin Neurons
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DOI：
10.1210/en.2014-1851
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发表时间：
2015-03-01
期刊：
影响因子：
4.8
通讯作者：
Levine, Jon E.
中科院分区：
文献类型：
--
作者：
Dubois, Sharon L.;Acosta-Martinez, Maricedes;Levine, Jon E.
下丘脑kisspeptin（Kiss 1）神经元表达雌激素受体α（ER α），并对雌性啮齿动物的GnRH/LH分泌发挥控制作用。已经提出，雌二醇（E-2）激活弓状核（ARC）内kisspeptin神经元的ER α抑制GnRH/LH分泌（负反馈），而E-2激活前腹侧室周核（AVPV）内kisspeptin神经元的ER α介导排卵前GnRH/LH峰的释放（正反馈）。为了验证这些假设，我们产生了Kisspeptin细胞特异性ER α缺失（KER α KO）的小鼠，并用E-2方案对它们进行治疗，这些方案对GnRH/LH分泌产生负反馈或正反馈作用。使用负反馈方案，正如预期的那样，E-2有效地抑制了卵巢切除（OVX）野生型（WT）小鼠的LH水平，达到卵巢完整小鼠的水平。然而，令人惊讶的是，尽管在KER α KO小鼠的ARC和AVPV中E-2对Kiss 1 mRNA表达的调节被废除，但E-2也有效地将OVX KER α KO小鼠中的LH水平降低至卵巢完整小鼠中观察到的水平。相反，使用正反馈方案，E-2刺激WT小鼠的LH峰，但对KER α KO小鼠无影响。这些实验清楚地表明，Kisspeptin神经元中的ER α是成年雌性小鼠中E-2对GnRH/LH分泌的正反馈作用所必需的，而不是负反馈作用。KER α KO小鼠未能表现出GnRH/LH峰是否反映了ER α在kisspeptin神经元发育中的作用，在导致GnRH/LH峰释放的主动信号传导过程中的作用，或两者兼而有之，仍有待确定。
Hypothalamic kisspeptin (Kiss1) neurons express estrogen receptor alpha (ER alpha) and exert control over GnRH/LH secretion in female rodents. It has been proposed that estradiol (E-2) activation of ER alpha in kisspeptin neurons in the arcuate nucleus (ARC) suppressesGnRH/LHsecretion (negative feedback), whereas E-2 activation of ER alpha 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 ER alpha (KER alpha KO) and treated them with E-2 regimens that evoke either negative or positive feedback actions on GnRH/LH secretion. Using negative feedback regimens, as expected, E-2 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 E-2 regulation of Kiss1 mRNA expression was abrogated in both the ARC and AVPV of KER alpha KO mice, E-2 also effectively decreased LH levels in OVX KER alpha KO mice to the levels seen in ovary-intact mice. Conversely, using a positive feedback regimen, E-2 stimulated LH surges in WT mice, but had no effect in KER alpha KO mice. These experiments clearly demonstrate that ER alpha in kisspeptin neurons is required for the positive, but not negative feedback actions of E-2 on GnRH/LH secretion in adult female mice. It remains to be determined whether the failure of KER alpha KO mice to exhibit GnRH/LH surges reflects the role of ER alpha in the development of kisspeptin neurons, in the active signaling processes leading to the release of GnRH/LH surges, or both.