Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator

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 neu...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2021-02, Vol.118 (5)
Main Authors: Nagae, Mayuko, Uenoyama, Yoshihisa, Okamoto, Saki, Tsuchida, Hitomi, Ikegami, Kana, Goto, Teppei, Majarune, Sutisa, Nakamura, Sho, Sanbo, Makoto, Hirabayashi, Masumi, Kobayashi, Kenta, Inoue, Naoko, Tsukamura, Hiroko
Format: Article
Language:English
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Biological Sciences
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Summary: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 isspeptin (encoded by ), eurokinin B (encoded by ), and norphin A serve as a GnRH pulse generator; however, no direct evidence is currently available. Here, we show that rescuing >20% KNDy neurons by transfecting inside arcuate neurons, but not outside of these neurons, recovered folliculogenesis and luteinizing hormone (LH) pulses, an indicator of GnRH pulses, in female global knockout (KO) rats and that >90% conditional arcuate KO in newly generated -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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2009156118