Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction
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.
No new dataset is generated or used in the current study.
Article and author information
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.
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.
- Joel K Elmquist, University of Texas Southwestern Medical Center, United States
- Received: December 9, 2018
- Accepted: April 2, 2019
- Accepted Manuscript published: April 4, 2019 (version 1)
- Version of Record published: April 30, 2019 (version 2)
© 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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