Sex specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2

  1. Silvia Leon
  2. Rajae Talbi
  3. Elizabeth A McCarthy
  4. Chrysanthi Fergani
  5. Kaitlin Ferrari
  6. Lydie Naule
  7. Ji Hae Choi
  8. Rona S Carroll
  9. Ursula B Kaiser
  10. Carlos F Aylwin
  11. Alejandro Lomniczi
  12. Víctor M Navarro  Is a corresponding author
  1. Harvard Medical School, United States
  2. Harvard Medical School and Brigham and Women's Hospital, United States
  3. Oregon National Primate Research Center, United States

Abstract

Hypothalamic Kiss1 neurons control gonadotropin-releasing hormone (GnRH) 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 (TF) 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 (LH) 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Silvia Leon

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Rajae Talbi

    Endocrinology, Harvard Medical School and Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elizabeth A McCarthy

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Chrysanthi Fergani

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7028-4158
  5. Kaitlin Ferrari

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lydie Naule

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ji Hae Choi

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Rona S Carroll

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ursula B Kaiser

    Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8237-0704
  10. Carlos F Aylwin

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Alejandro Lomniczi

    Oregon National Primate Research Center, Beaverton, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Víctor M Navarro

    Harvard Medical School, Boston, United States
    For correspondence
    vnavarro@bwh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5799-219X

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD090151)

  • Víctor M Navarro

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD099084)

  • Víctor M Navarro

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD095383)

  • Víctor M Navarro

Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD097963)

  • Elizabeth A McCarthy

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD084542)

  • Alejandro Lomniczi

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD019938)

  • Ursula B Kaiser

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD082314)

  • Ursula B Kaiser

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal care and experimental procedures were approved by the National Institute of Health, and Brigham and Women's Hospital Institutional Animal Care and Use Committee, protocol #05165. The Brigham and Women's Hospital is a registered research facility with the U.S. Department of Agriculture (#14-19), is accredited by the American Association for the Accreditation of Laboratory Animal Care and meets the National Institutes of Health standards as set forth in the Guide for the Care and Use of Laboratory Animals (DHHS Publication No. (NIH) 85-23 Revised 1985).

Reviewing Editor

  1. Margaret M McCarthy, University of Maryland School of Medicine, United States

Publication history

  1. Received: April 25, 2021
  2. Accepted: September 3, 2021
  3. Accepted Manuscript published: September 8, 2021 (version 1)
  4. Version of Record published: September 14, 2021 (version 2)

Copyright

© 2021, Leon et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Silvia Leon
  2. Rajae Talbi
  3. Elizabeth A McCarthy
  4. Chrysanthi Fergani
  5. Kaitlin Ferrari
  6. Lydie Naule
  7. Ji Hae Choi
  8. Rona S Carroll
  9. Ursula B Kaiser
  10. Carlos F Aylwin
  11. Alejandro Lomniczi
  12. Víctor M Navarro
(2021)
Sex specific pubertal and metabolic regulation of Kiss1 neurons via Nhlh2
eLife 10:e69765.
https://doi.org/10.7554/eLife.69765

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