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首页> 外文期刊>Endocrinology >Effects of neuron-specific Estrogen Receptor (ER) α and ERβ deletion on the acute estrogen negative feedback mechanism in adult female mice
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Effects of neuron-specific Estrogen Receptor (ER) α and ERβ deletion on the acute estrogen negative feedback mechanism in adult female mice

机译：神经元特异性雌激素受体（ER）和ERβ缺失对成年雌性小鼠急性雌激素负反馈机制的影响

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摘要

The negative feedback mechanism through which 17β-estradiol (E 2) acts to suppress the activity of the GnRH neurons remains unclear. Using inducible and cell-specific genetic mouse models, we examined the estrogen receptor (ER) isoforms expressed by neurons that mediate acute estrogen negative feedback. Adult female mutant mice in which ERα was deleted from all neurons in the neonatal period failed to exhibit estrous cycles or negative feedback. Adult mutant female mice with neonatal neuronal ERβ deletion exhibited normal estrous cycles, but a failure of E2 to suppress LH secretion was seen in ovariectomized mice. Mutant mice with a GnRH neuron-selective deletion of ERβ exhibited normal cycles and negative feedback, suggesting no critical role for ERβ in GnRH neurons in acute negative feedback. To examine the adult roles of neurons expressing ERα, an inducible tamoxifen-based Cre-LoxP approach was used to ablate ERα from neurons that express calmodulin kinase IIα in adults. This resulted in mice with no estrous cycles, a normal increase in LH after ovariectomy, but an inability of E2 to suppress LH secretion. Finally, acute administration of ERα- and ERβ-selective agonists to adult ovariectomized wild-type mice revealed that activation of ERα suppressed LH secretion, whereas ERβ agonists had no effect. This study highlights the differences in adult reproductive phenotypes that result from neonatal vs adult ablation of ERα in the brain. Together, these experiments expand previous global knockout studies by demonstrating that neurons expressing ERα are essential and probably sufficient for the acute estrogen negative feedback mechanism in female mice.
机译：17β-雌二醇（E 2）通过其抑制GnRH神经元活性的负反馈机制仍不清楚。使用诱导型和细胞特异性遗传小鼠模型，我们检查了介导急性雌激素负反馈的神经元表达的雌激素受体（ER）亚型。在新生期从所有神经元中缺失ERα的成年雌性突变小鼠未能表现出发情周期或负反馈。新生神经元ERβ缺失的成年突变雌性小鼠表现出正常的发情周期，但在去卵巢小鼠中发现E2不能抑制LH分泌。带有ERβ的GnRH神经元选择性缺失的突变小鼠表现出正常的周期和负反馈，表明在急性负反馈中GnRH神经元中ERβ没有关键作用。为了检查表达ERα的神经元在成人中的作用，使用了基于他莫昔芬的可诱导的Cre-LoxP方法从成年人中表达钙调蛋白激酶IIα的神经元中消除ERα。这导致小鼠没有发情周期，卵巢切除术后LH正常增加，但是E2无法抑制LH分泌。最后，对成年卵巢切除的野生型小鼠急性给予ERα和ERβ选择性激动剂表明，激活ERα抑制了LH分泌，而ERβ激动剂则没有作用。这项研究强调了大脑中ERα的新生儿和成人消融导致的成人生殖表型的差异。总之，这些实验通过证明表达ERα的神经元对于雌性小鼠的急性雌激素负反馈机制至关重要，并且可能已经足够，从而扩展了之前的全球基因敲除研究。

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