DESCRIPTION (provided by applicant): Gonadotropin-releasing hormone (GnRH) is a neurohomrone responsible for the activation and maintenance of reproduction. Neurons that synthesize GnRH must undergo complex maturational processes during development to become a functional system capable of supporting reproduction. Once mature, the GnRH system also needs to remain functional for an appropriate duration to ensure the propagation of offspring. Thus, one's reproductive health is critically dependent on factors that orchestrate the formation and maintenance of the GnRH system. The goal of the proposed study is to understand how a group of signaling molecules, fibroblast growth factors (FGFs), and their receptors (FGFRs) regulate the developmental maturation and postnatal functionality of the GnRH system. A number of transgenic mouse models, each lacking a distinct component of the FGF signaling system, will be used to investigate if these deficiencies result in the aberrant formation or maintenance of the GnRH system, ultimately leading to sterility. In vitro culture methods, morphological analysis, gene expression studies, electrophysiology, and whole animal manipulation will be utilized for this purpose. This research is highly relevant to public health because mutations on one of the FGFRs lead to human disorders characterized by reproductive failure. Understanding how FGFs and FGFRs regulate the GnRH system could provide important insights into the nature of GnRH system disruption in these individuals. In addition, it will reveal if mutations on other genes encoding FGFs/FGFRs are also candidates for these human disorders. PUBLIC HEALTH RELEVANCE: In all mammals including humans, the secretion of a hormone called gonadotropin- releasing hormone (GnRH) from the brain is required to initiate and maintain reproduction. A very small population of cells (about 800-3000 cells) in the brain produces GnRH. During embryogenesis, these cells first arise in the nose and then migrate to the brain where they eventually settle and assume their function. If the process of maturation (including migration and other aspects) is disturbed in these cells, the animal will lose the normal ability to secrete GnRH and suffer serious fertility problems. As such, it becomes essential to identify factors that are critical in the regulation of these cells. In the previous grant period, we identified a group of factors called fibroblast growth factors (FGFs) as important regulators that drive the maturational changes of GnRH-producing cells. Since there are 22 FGFs and 4 receptors for FGFs, we need to begin to pinpoint exactly which of these is (are) absolutely critical for the maturation of GnRH-producing cells and thus fertility. This proposal aims to investigate the roles of one FGF and two receptors for FGFs in inducing the maturation of GnRH-producing cells. In addition, we will investigate if these FGF and FGF receptors are needed to maintain the health of GnRH-producing cells as the animal ages, thereby preventing the premature termination of reproductive function. The proposed studies are of great clinical relevance since they identify candidate FGF and receptor genes whose mutations could cause reproductive anomalies in humans. Further, these studies allow us to probe, at the basic science level, the actual mechanisms induced by FGFs to stimulate the function of GnRH-producing cells. This will provide insights into what changes are required to make a functional hormone- producing cell.

PROJECT NARRATIVE In all mammals including humans, the secretion of a hormone called gonadotropin- releasing hormone (GnRH) from the brain is required to initiate and maintain reproduction. A very small population of cells (about 800-3000 cells) in the brain produces GnRH. During embryogenesis, these cells first arise in the nose and then migrate to the brain where they eventually settle and assume their function. If the process of maturation (including migration and other aspects) is disturbed in these cells, the animal will lose the normal ability to secrete GnRH and suffer serious fertility problems. As such, it becomes essential to identify factors that are critical in the regulation of these cells. In the previous grant period, we identified a group of factors called fibroblast growth factors (FGFs) as important regulators that drive the maturational changes of GnRH-producing cells. Since there are 22 FGFs and 4 receptors for FGFs, we need to begin to pinpoint exactly which of these is (are) absolutely critical for the maturation of GnRH-producing cells and thus fertility. This proposal aims to investigate the roles of one FGF and two receptors for FGFs in inducing the maturation of GnRH-producing cells. In addition, we will investigate if these FGF and FGF receptors are needed to maintain the health of GnRH-producing cells as the animal ages, thereby preventing the premature termination of reproductive function. The proposed studies are of great clinical relevance since they identify candidate FGF and receptor genes whose mutations could cause reproductive anomalies in humans. Further, these studies allow us to probe, at the basic science level, the actual mechanisms induced by FGFs to stimulate the function of GnRH-producing cells. This will provide insights into what changes are required to make a functional hormone- producing cell.