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Sex-specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2.

Leon, S, Talbi, R, McCarthy, EA, Ferrari, K, Fergani, C, Naule, L, Choi, JH, Carroll, RS, Kaiser, UB, Aylwin, CF, Lomniczi, A and Navarro, VM (2021) Sex-specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2. eLife, 10. ISSN 2050-084X

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Hypothalamic Kiss1 neurons control gonadotropin-releasing hormone release through the secretion of kisspeptin. Kiss1 neurons serve as a nodal center that conveys essential regulatory cues for the attainment and maintenance of reproductive function. Despite this critical role, the mechanisms that control kisspeptin synthesis and release remain largely unknown. Using Drop-Seq data from the arcuate nucleus of adult mice and in situ hybridization, we identified Nescient Helix-Loop-Helix 2 (Nhlh2), a transcription factor of the basic helix-loop-helix family, to be enriched in Kiss1 neurons. JASPAR analysis revealed several binding sites for NHLH2 in the Kiss1 and Tac2 (neurokinin B) 5' regulatory regions. In vitro luciferase assays evidenced a robust stimulatory action of NHLH2 on human KISS1 and TAC3 promoters. The recruitment of NHLH2 to the KISS1 and TAC3 promoters was further confirmed through chromatin immunoprecipitation. In vivo conditional ablation of Nhlh2 from Kiss1 neurons using Kiss1Cre:Nhlh2fl/fl mice induced a male-specific delay in puberty onset, in line with a decrease in arcuate Kiss1 expression. Females retained normal reproductive function albeit with irregular estrous cycles. Further analysis of male Kiss1Cre:Nhlh2fl/fl mice revealed higher susceptibility to metabolic challenges in the release of luteinizing hormone and impaired response to leptin. Overall, in Kiss1 neurons, Nhlh2 contributes to the metabolic regulation of kisspeptin and NKB synthesis and release, with implications for the timing of puberty onset and regulation of fertility in male mice.

Item Type: Article
Uncontrolled Keywords: 0601 Biochemistry and Cell Biology
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
Q Science > QP Physiology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: Biological & Environmental Sciences (from Sep 19)
Publisher: eLife Sciences Publications Ltd
Related URLs:
Date Deposited: 24 Sep 2021 12:06
Last Modified: 24 Sep 2021 12:06
DOI or ID number: 10.7554/eLife.69765
URI: https://researchonline.ljmu.ac.uk/id/eprint/15549
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