FGF Regulation of GnRH Neurons

说明(申请人提供)：促性腺激素释放激素(GnRH)是一种神经激素，负责激活和维持生殖。合成促性腺激素释放激素的神经元在发育过程中必须经历复杂的成熟过程，才能成为支持生殖的功能系统。一旦成熟，GnRH系统还需要在适当的时间内保持功能，以确保后代的繁殖。因此，一个人的生殖健康严重依赖于协调GnRH系统形成和维持的因素。这项研究的目的是了解一组信号分子、成纤维细胞生长因子(FGFs)及其受体(FGFRs)如何调节GnRH系统的发育成熟和出生后功能。许多转基因小鼠模型，每个模型都缺乏成纤维细胞生长因子信号系统的不同组成部分，将被用来调查这些缺陷是否导致GnRH系统的异常形成或维持，最终导致不育。将利用体外培养方法、形态分析、基因表达研究、电生理学和整个动物操作来实现这一目的。这项研究与公共卫生高度相关，因为其中一种FGFR的突变会导致以生殖障碍为特征的人类疾病。了解FGFs和FGFRs如何调节GnRH系统，可以为这些人的GnRH系统破坏的性质提供重要的见解。此外，它还将揭示编码FGFs/FGFRs的其他基因上的突变是否也是这些人类疾病的候选基因。与公共卫生相关：在包括人类在内的所有哺乳动物中，大脑需要分泌一种名为促性腺激素释放激素(GnRH)的激素来启动和维持生殖。大脑中的一小部分细胞(大约800-3000个细胞)会产生促性腺激素释放激素。在胚胎发育过程中，这些细胞首先出现在鼻子里，然后迁移到大脑，在那里它们最终定居并承担起自己的功能。如果这些细胞的成熟过程(包括迁移等方面)受到干扰，动物将失去正常分泌GnRH的能力，并遭受严重的生育问题。因此，确定对这些细胞的调控至关重要的因素就变得至关重要。在之前的资助期间，我们确定了一组称为成纤维细胞生长因子(FGFs)的因子是驱动GnRH产生细胞成熟变化的重要调节因素。由于有22个FGFs和4个FGFs受体，我们需要开始准确地确定其中哪一个对于GnRH产生细胞的成熟和生育是绝对关键的。本研究旨在探讨一种成纤维细胞生长因子和两种成纤维细胞生长因子受体在促性腺激素释放激素生成细胞成熟中的作用。此外，我们还将研究随着动物年龄的增长，是否需要这些成纤维细胞生长因子和成纤维细胞生长因子受体来维持产生促性腺激素释放激素的细胞的健康，从而防止生殖功能的过早终止。这项拟议的研究具有重要的临床意义，因为它们确定了候选的成纤维细胞生长因子和受体基因，这些基因的突变可能导致人类生殖异常。此外，这些研究使我们能够在基础科学水平上探索FGFs刺激GnRH产生细胞功能的实际机制。这将为制造具有功能的激素产生细胞所需的改变提供洞察力。

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.