Deficiency of arcuate nucleus kisspeptin results in postpubertal central hypogonadism.
Deficiency of arcuate nucleus kisspeptin results in postpubertal central hypogonadism.
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DOI：
10.1152/ajpendo.00088.2021
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发表时间：
2021-08-01
期刊：
影响因子：
--
通讯作者：
Radovick S
中科院分区：
文献类型：
--
作者：
Nandankar N;Negrón AL;Wolfe A;Levine JE;Radovick S
Kisspeptin（由Kiss 1编码）是一种神经内分泌调节生殖的重要神经肽，主要在下丘脑室周围前腹核（AVPV）和弓状核（ARC）合成。AVPV kisspeptin被认为调节雌激素诱导的促性腺激素释放激素（GnRH）和促黄体生成激素（LH）的正反馈控制，以及女性排卵前LH峰。与此相反，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），被认为是介导雌激素诱导的GnRH/LH负反馈控制和脉冲式GnRH/LH释放的主要调节剂。然而，明确的数据来描绘AVPV与ARC kisspeptin神经元在控制GnRH/LH释放的具体作用是缺乏的。因此，我们产生了一种新的小鼠模型，靶向删除Kiss1的ARC核（Pdyn-Cre/Kiss1fl/fl KO），以确定ARC和AVPV kisspeptin神经元之间的功能差异的生殖轴。在mRNA和蛋白质水平上证实了敲除的功效。与对照组相比，成年雌性Pdyn-Cre/Kiss1fl/fl KO小鼠表现出持续的间情期和显著较少的LH脉冲，导致卵泡发生停滞、性腺功能减退和不育。Pdyn-Cre/Kiss1fl/fl KO雄性动物还表现出LH脉动性中断、性腺功能减退和可变的精子发生缺陷和生育力低下。雄性和雌性动物的青春期开始时间与对照组相同。这些发现增加了目前的证据，证明ARC KNDy神经元中的kisspeptin在两种性别的GnRH/LH脉动中起着关键作用，同时直接建立了ARC kisspeptin在调节雌性小鼠的发情周期和两种性别的配子发生中的作用，并最终导致生育能力中断。Pdyn-Cre/Kiss1fl/fl KO小鼠是一种新的青春期后中枢性腺功能减退的哺乳动物模型。我们通过一种新的条件性敲除KNDy神经元中弓状核（ARC）特异性kisspeptin的小鼠模型证明，ARC kisspeptin对雌性小鼠的发情周期和两性小鼠的GnRH/LH脉动至关重要。我们的研究表明，ARC kisspeptin对正常配子发生是必不可少的，ARC kisspeptin的缺失会导致显著的性腺功能减退，影响生育能力。我们的研究结果进一步证实，正常的青春期发生，尽管ARC kisspeptin的损失。
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 preovulatory LH surge in females. In contrast, ARC kisspeptin neurons, which largely coexpress 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/Kiss1fl/fl KO) to determine the functional differences between ARC and AVPV kisspeptin neurons on the reproductive axis. The efficacy of the knockout was confirmed at both the mRNA and protein levels. Adult female Pdyn-Cre/Kiss1fl/fl KO mice exhibited persistent diestrus and significantly fewer LH pulses when compared with controls, resulting in arrested folliculogenesis, hypogonadism, and infertility. Pdyn-Cre/Kiss1fl/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/Kiss1fl/fl KO mice present a novel mammalian model of postpubertal central hypogonadism. NEW & NOTEWORTHY We demonstrate through a novel, conditional knockout mouse model of arcuate nucleus (ARC)-specific kisspeptin in the KNDy neuron that ARC kisspeptin is critical for estrous cyclicity in female mice and GnRH/LH pulsatility in both sexes. Our study reveals that ARC kisspeptin is essential for normal gametogenesis, and the loss of ARC kisspeptin results in significant hypogonadism, impacting fertility status. Our findings further confirm that normal puberty occurs despite a loss of ARC kisspeptin.
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影响因子：
3.4
作者：
Adams C;Chen X;Moenter SM
通讯作者：
Moenter SM
影响因子：
4.8
作者：
de Croft, Simon;Piet, Richard;Herbison, Allan E.
通讯作者：
Herbison, Allan E.
DOI：
10.1073/pnas.1415226112
发表时间：
2014-12-23
影响因子：
11.1
作者：
Campos, Pauline;Herbison, Allan E.
通讯作者：
Herbison, Allan E.
DOI：
10.1073/pnas.1834399100
发表时间：
2003-09-16
影响因子：
11.1
作者：
de Roux, N;Genin, E;Milgrom, E
通讯作者：
Milgrom, E
影响因子：
3.1
作者：
Craig, Jesse;Orisaka, Makoto;Tsang, Benjamin K.
通讯作者：
Tsang, Benjamin K.