Kisspeptin (encoded by Kiss1), a neuropeptide critically involved in neuroendocrine regulation of reproduction, is primarily synthesized in two hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). AVPV kisspeptin is thought to regulate the estrogen-induced positive feedback control of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), and the pre-ovulatory LH surge in females. In contrast, ARC kisspeptin neurons, which largely co-express neurokinin B and dynorphin A (collectively named KNDy neurons), are thought to mediate estrogen-induced negative feedback control of GnRH/LH and be the major regulators of pulsatile GnRH/LH release. However, definitive data to delineate the specific roles of AVPV versus ARC kisspeptin neurons in the control of GnRH/LH release is lacking. Therefore, we generated a novel mouse model targeting deletion of Kiss1 to the ARC nucleus (Pdyn-Cre/Kiss1^fl/fl KO) to determine the functional differences between ARC and AVPV kisspeptin neurons on the reproductive axis. The efficacy of the knock-out was confirmed at both the mRNA and protein levels. Adult female Pdyn-Cre/Kiss1^fl/fl KO mice exhibited persistent diestrus and significantly fewer LH pulses when compared to controls, resulting in arrested folliculogenesis, hypogonadism, and infertility. Pdyn-Cre/Kiss1^fl/fl KO males also exhibited disrupted LH pulsatility, hypogonadism, and variable, defective spermatogenesis and subfertility. The timing of pubertal onset in males and females was equivalent to controls. These findings add to the current body of evidence for the critical role of kisspeptin in ARC KNDy neurons in GnRH/LH pulsatility in both sexes, while directly establishing ARC kisspeptin's role in regulating estrous cyclicity in female mice, and gametogenesis in both sexes, and culminating in disrupted fertility. The Pdyn-Cre/Kiss1^fl/fl KO mice present a novel mammalian model of post-pubertal central hypogonadism.

中文翻译：

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弓状核 Kisspeptin 缺乏导致青春期后中枢性性腺功能减退症


Kisspeptin（由 Kiss1 编码）是一种关键参与生殖神经内分泌调节的神经肽，主要在两个下丘脑核中合成：前腹侧室周核 (AVPV) 和弓状核 (ARC)。 AVPV Kisspeptin 被认为可以调节雌激素诱导的促性腺激素释放激素 (GnRH) 和黄体生成素 (LH) 的正反馈控制，以及女性排卵前 LH 的激增。相比之下，ARC Kisspeptin 神经元主要共表达神经激肽 B 和强啡肽 A（统称为 KNDy 神经元），被认为介导雌激素诱导的 GnRH/LH 负反馈控制，并且是脉冲式 GnRH/LH 释放的主要调节因子。然而，缺乏明确的数据来描述 AVPV 与 ARC Kisspeptin 神经元在控制 GnRH/LH 释放中的具体作用。因此，我们构建了一种针对 ARC 核 Kiss1 缺失的新型小鼠模型 (Pdyn-Cre/Kiss1 ^fl/fl KO)，以确定 ARC 和 AVPV Kisspeptin 神经元在生殖轴上的功能差异。敲除的功效在 mRNA 和蛋白质水平上得到了证实。与对照组相比，成年雌性 Pdyn-Cre/Kiss1 ^fl/fl KO 小鼠表现出持续的动情间期和明显较少的 LH 脉冲，导致卵泡发生停滞、性腺功能减退和不育。 Pdyn-Cre/Kiss1 ^fl/fl KO 雄性还表现出 LH 搏动紊乱、性腺功能减退以及可变的、有缺陷的精子发生和生育力低下。男性和女性青春期开始的时间与对照组相同。 这些发现为目前的证据提供了证据，证明 Kisspeptin 在 ARC KNDy 神经元中对两性 GnRH/LH 搏动的关键作用，同时直接确立了 ARC Kisspeptin 在调节雌性小鼠动情周期和两性配子发生中的作用，并最终生育能力受到干扰。 Pdyn-Cre/Kiss1 ^fl/fl KO 小鼠提出了一种新的青春期后中枢性腺功能减退症哺乳动物模型。