Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator
Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator
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DOI：
10.1073/pnas.2009156118
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发表时间：
2021-02-02
影响因子：
11.1
通讯作者：
Tsukamura, Hiroko
中科院分区：
文献类型：
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作者：
Nagae, Mayuko;Uenoyama, Yoshihisa;Tsukamura, Hiroko
促性腺激素释放激素 (GnRH) 脉冲对于哺乳动物生殖至关重要：不孕妇女需要 GnRH 脉冲疗法作为治疗方法，因为连续 GnRH 治疗会矛盾地抑制促性腺激素释放。间接证据表明，下丘脑弓状 KNDy 神经元表达 Kisspeptin（由 Kiss1 编码）、神经激肽 B（由 Tac3 编码）和 lynorphin A 作为 GnRH 脉冲发生器；然而，目前还没有直接证据。在这里，我们表明，通过在弓形 Tac3 神经元内部转染 Kiss1（而不是在这些神经元外部）来拯救 >20% KNDy 神经元，在雌性整体 Kiss1 敲除 (KO) 大鼠中恢复了卵泡发生和黄体生成素 (LH) 脉冲（GnRH 脉冲的指标），并且在新生的 Kiss/-floxed 大鼠中 >90% 条件性弓形 Kiss1 KO 完全抑制了 LH 脉冲。这些结果首先提供了直接证据表明KNDy神经元是GnRH脉冲发生器，并且至少20%的KNDy神经元足以通过产生GnRH/促性腺激素脉冲来维持卵泡发生。
The gonadotropin-releasing hormone (GnRH) pulse is fundamental for mammalian reproduction: GnRH pulse regimens are needed as therapies for infertile women as continuous GnRH treatment paradoxically inhibits gonadotropin release. Circumstantial evidence suggests that the hypothalamic arcuate KNDy neurons expressing kisspeptin (encoded by Kiss1), neurokinin B (encoded by Tac3), and ilynorphin A serve as a GnRH pulse generator; however, no direct evidence is currently available. Here, we show that rescuing >20% KNDy neurons by transfecting Kiss1 inside arcuate Tac3 neurons, but not outside of these neurons, recovered folliculogenesis and luteinizing hormone (LH) pulses, an indicator of GnRH pulses, in female global Kiss1 knockout (KO) rats and that >90% conditional arcuate Kiss1 KO in newly generated Kiss/-floxed rats completely suppressed LH pulses. These results first provide direct evidence that KNDy neurons are the GnRH pulse generator, and at least 20% of KNDy neurons are sufficient to maintain folliculogenesis via generating GnRH/gonadotropin pulses.