Gonadotropin-releasing hormone (GnRH) neurons drive reproductive activation in all vertebrates. Fibroblast growth factor (Fgf) signaling is required for the early development of GnRH neurons, but its role in the postnatal maintenance of GnRH neurons is less clear. Recent data from the PI's lab reveal that Fgf signaling deficiency leads to a significant loss of postnatal GnRH neurons in mice, but this loss can be reversed by early environmental intervention in the form of opposite-sex (OS) housing. These novel results suggest the postnatal GnRH system, like the cognitive brain, is highly plastic and responsive to experience-altering environmental stimuli. The overarching goals of this proposal are to examine the cellular processes responsible for the loss of postnatal GnRH neurons in Fgf signaling-deficient animals, and to identify molecular mechanisms and upstream cues triggered by OS housing to reverse GnRH neuronal loss in Fgf signaling- deficient mice. These goals will be accomplished by three specific aims.
Aim 1 will use a lineage tracing technique to test if Fgf signaling deficiency leads sequentially to the de-dedifferentiation and then death of postnatal GnRH neurons.
Aim 2 will first use RNA-seq to identify genes differentially regulated by OS housing. Following, the candidate factors will be validated by qPCR and as permitted by mouse models, tested in whole animals to confirm their roles in reversing the postnatal GnRH neuronal loss.
Aim 3 will determine if pheromones and elevated androgens are two upstream cues triggered by OS housing to reactivate the failing GnRH system. Collectively, the proposed studies will be important for demonstrating that the postnatal reproductive brain is not a static structure. Instead, its integrity and function are dynamically modulated by environmental cues and perhaps one's lifestyle choices and experience. This information can be used to improve the reproductive health of GnRH-deficient humans by manipulating the highly plastic postnatal GnRH system via suitable environmental means.

Public Health Relevance

Identifying environmental cues that can influence postnatal GnRH neurons will provide insights into the general nature of environmental signals to adopt or avoid for fertility improvement. These insights will benefit fertility in individuals with diverse mutations that compromise the GnRH system.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD083260-03
Application #
9477059
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Ravindranath, Neelakanta
Project Start
2016-07-26
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80303