Disrupted Kisspeptin Signaling in GnRH Neurons Leads to Hypogonadotrophic Hypogonadism
Disrupted Kisspeptin Signaling in GnRH Neurons Leads to Hypogonadotrophic Hypogonadism
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DOI：
10.1210/me.2013-1319
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发表时间：
2014-02-01
影响因子：
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通讯作者：
Radovick, Sally
中科院分区：
文献类型：
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作者：
Novaira, Horacio J.;Sonko, Momodou L.;Radovick, Sally
具有里程碑意义的研究表明，Kisspeptin 和 Kisspeptin 受体 (Kiss1r) 的突变会导致人类和基因改造小鼠模型的生殖功能障碍。然而，由于 Kisspeptin 及其受体存在于中枢和外周生殖轴的靶细胞中，因此致病信号的精确位置尚不清楚。本文描述的研究表明，GnRH 神经元中的 Kisspeptin-Kiss1r 信号通路对于青春期的开始以及正常生殖功能的实现至关重要。在本研究中，我们直接检验了 Kisspeptin 神经元通过激活 GnRH 神经元质膜上的 Kiss1r 来调节 GnRH 分泌的假设。生成 GnRH 神经元特异性 Kiss1r 敲除小鼠模型 (GKirKO)，并评估生殖发育和表型。雌性和雄性 GKirKO 小鼠均不育，血清 LH 和 FSH 水平较低。 GKirKO 男性存在外部异常，例如小阴茎和与包皮腺分离失败相关的肛门生殖器距离缩短。在雌性 GKirKO 小鼠中观察到青春期开始延迟和动情周期异常。总而言之，这些数据提供了体内证据表明 GnRH 神经元中的 Kiss1r 对于生殖发育和生育能力至关重要。
Landmark studies have shown that mutations in kisspeptin and the kisspeptin receptor (Kiss1r) result in reproductive dysfunction in humans and genetically altered mouse models. However, because kisspeptin and its receptor are present in target cells of the central and peripheral reproductive axis, the precise location(s) for the pathogenic signal is unknown. The study described herein shows that the kisspeptin-Kiss1r signaling pathway in the GnRH neuron is singularly critical for both the onset of puberty as well as the attainment of normal reproductive function. In this study, we directly test the hypothesis that kisspeptin neurons regulate GnRH secretion through the activation of Kiss1r on the plasma membrane of GnRH neurons. A GnRH neuron-specific Kiss1r knockout mouse model (GKirKO) was generated, and reproductive development and phenotype were assessed. Both female and male GKirKO mice were infertile, having low serum LH and FSH levels. External abnormalities such as microphallus and decreased anogenital distance associated with failure of preputial gland separation were present in GKirKO males. A delay in pubertal onset and abnormal estrous cyclicity were observed in female GKirKO mice. Taken together, these data provide in vivo evidence that Kiss1r in GnRH neurons is critical for reproductive development and fertility.