Analysis of Multiple Positive Feedback Paradigms Demonstrates a Complete Absence of LH Surges and GnRH Activation in Mice Lacking Kisspeptin Signaling
Analysis of Multiple Positive Feedback Paradigms Demonstrates a Complete Absence of LH Surges and GnRH Activation in Mice Lacking Kisspeptin Signaling
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DOI：
10.1095/biolreprod.113.108555
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发表时间：
2013-06-01
影响因子：
3.6
通讯作者：
Kauffman, Alexander S.
中科院分区：
文献类型：
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作者：
Dror, Tal;Franks, Jennifer;Kauffman, Alexander S.
Kisspeptin通过Kiss 1 r受体刺激促性腺激素释放激素（GnRH）神经元。在啮齿类动物中，下丘脑吻端的雌激素反应性kisspeptin神经元被认为介导雌激素诱导的排卵前促黄体生成激素（LH）峰的正反馈诱导。然而，关于缺乏Kiss 1 r的小鼠对外源性激素的反应显示LH激增的能力存在相互矛盾的证据。这种差异是否反映了使用的不同小鼠品系和/或不同浪涌诱导范例的利用尚不清楚。在这里，我们在一个Kiss 1 r敲除（KO）模型中测试了多种激素范式，以了解哪些范式（如果有的话）可以产生昼夜节律定时的LH激增。切除Kiss 1 r KO和野生型（WT）雌性动物的卵巢，以各种方式给予性类固醇，并在几天后评估早晨或晚上（发生激增时）的LH水平。血清LH水平非常低，在所有早晨的动物，无论基因型或激素的范例。在每个范例中，几乎所有WT雌性动物在晚上均显示出明显的LH峰，而KO雌性动物均未显示LH峰。KO小鼠中LH峰的缺乏反映了GnRH分泌的缺乏，而不是由于终生缺乏GnRH暴露而导致的垂体反应性降低，因为KO小鼠对GnRH引发有强烈的LH分泌反应。此外，WT雌性动物在晚上检测到高cfos-GnRH共表达，而KO雌性动物在所有时间点均存在低cfos-GnRH共表达。我们的研究结果最终表明，野生型女性一贯显示LH浪涌下多种激素的范例，而Kiss 1 r基因敲除小鼠没有，表明kisspeptin-Kiss 1 r信号是强制性的GnRH/LH浪涌诱导。
Kisspeptin stimulates gonadotropin-releasing hormone (GnRH) neurons via the kisspeptin receptor, Kiss1r. In rodents, estrogen-responsive kisspeptin neurons in the rostral hypothalamus have been postulated to mediate estrogen-induced positive feedback induction of the preovulatory luteinizing hormone (LH) surge. However, conflicting evidence exists regarding the ability of mice lacking Kiss1r to display LH surges in response to exogenous hormones. Whether the discrepancy reflects different mouse strains used and/or utilization of different surge-induction paradigms is unknown. Here, we tested multiple hormonal paradigms in one Kiss1r knockout (KO) model to see which paradigms, if any, could generate circadian-timed LH surges. Kiss1r KO and wild-type (WT) females were ovariectomized, given sex steroids in various modes, and assessed several days later for LH levels in the morning or evening (when surges occur). Serum LH levels were very low in all morning animals, regardless of genotype or hormonal paradigm. In each paradigm, virtually all WT females displayed clear LH surges in the evening, whereas none of the KO females demonstrated LH surges. The lack of LH surges in KO mice reflects a lack of GnRH secretion rather than diminished pituitary responsiveness from a lifetime lack of GnRH exposure because KO mice responded to GnRH priming with robust LH secretion. Moreover, high cfos-GnRH coexpression was detected in WT females in the evening, whereas low cfos-GnRH coexpression was present in KO females at all time points. Our findings conclusively demonstrate that WT females consistently display LH surges under multiple hormonal paradigms, whereas Kiss1r KO mice do not, indicating that kisspeptin-Kiss1r signaling is mandatory for GnRH/LH surge induction.