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Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

Research Article
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Cite this article as: eLife 2019;8:e43999 doi: 10.7554/eLife.43999

Abstract

The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedback are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally-controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.

Article and author information

Author details

  1. Luhong Wang

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Charlotte Vanacker

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Laura L Burger

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tammy Barnes

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yatrik M Shah

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Martin G Myers

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Suzanne M Moenter

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    For correspondence
    smoenter@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9812-0497

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (Principle Investigator Grants)

  • Suzanne M Moenter

National Institute of Diabetes and Digestive and Kidney Diseases (Center Core Grants)

  • Martin G Myers

Eunice Kennedy Shriver National Institute of Child Health and Human Development (Center Core Grants)

  • Suzanne M Moenter

National Institute of Diabetes and Digestive and Kidney Diseases (Principle Investigator Grants)

  • Yatrik M Shah

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (Pro 000006816 and Pro000008797) of the University of Michigan. The protocol was approved by the University of Michigan Institutional Animal Care and Use Committee. Every effort was made to minimize suffering.

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: December 9, 2018
  2. Accepted: April 2, 2019
  3. Accepted Manuscript published: April 4, 2019 (version 1)
  4. Version of Record published: April 30, 2019 (version 2)

Copyright

© 2019, Wang 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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