Fibroblast Growth Factor Regulation of Gonadotropin-Releasing Hormone Neurons

描述（由申请人提供）：促性腺激素释放激素（GnRH）神经元对各种脊椎动物生殖功能的启动和维持至关重要。在发育过程中，GnRH神经元进入连续阶段，成熟为能够支持成年生殖的功能网络。这些阶段包括嗅觉基板中的细胞命运特化、迁移到前脑以及将轴突靶向到正中隆起以释放激素。触发GnRH神经元进入这些阶段的信号，以及在每个阶段内调节成熟的因素在很大程度上仍然未知。我们假设神经营养因子提供时间特异性信号来驱动GnRH神经元发育的进展。在这项提案中，我们将使用一个候选的神经营养因子的方法，并专注于一个家庭的生长因子的行动，显示有深刻的神经营养活动在培养的原代和永生化的GnRH神经元：成纤维细胞生长因子（FGF）。此外，胰岛素样生长因子I（IGF-I），一种神经营养因子先前显示独立和/或协同FGF-2的作用，将进行研究。本提案将利用现有转基因模型和原代GnRH神经元培养物的组合，以实现以下目标：确定1）FGF的受体在发育期间是否以时间特异性方式表达，2）FGF是否改变GnRH祖细胞扩增和GnRH神经元的出现，3）FGF是否改变GnRH神经元向前脑的迁移，4）FGF是否促进GnRH轴突靶向，5）IGF-I是否单独或与FGF协同作用促进GnRH神经元存活。总之，这些目标的结果将提供重要的线索，关于神经内分泌系统的脊椎动物生殖的关键发展和成熟的神经营养因子的指导。此外，这些结果将有助于了解GnRH缺乏导致发育生殖异常的细胞和分子基础。

DESCRIPTION (provided by applicant): Gonadotropin-releasing hormone (GnRH) neurons are central to the initiation and maintenance of reproductive function in diverse vertebrates. During development, GnRH neurons enter sequential stages to mature into a functional network capable of supporting reproduction in adulthood. These stages include cell fate specification in the olfactory placodes, migration into the forebrain, and targeting of axons to the median eminence for hormone release. Signals that trigger GnRH neuronal entrance into these stages, as well as factors that regulate maturation within each stage remain largely unknown. We hypothesize that neurotrophic factors provide time-specific signals to drive the progression of GnRH neurons development. In this proposal, we will use a candidate neurotrophic factor approach and focus on the actions of a family of growth factors shown to have profound neurotrophic activities in cultured primary and immortalized GnRH neurons: the fibroblast growth factors (FGFs). Further, the actions of insulin-like growth factor I (IGF-I), a neurotrophic factor previously shown to act independently and/or collaboratively with FGF-2, will be investigated. This proposal will utilize a combination of existing transgenic models and primary GnRH neuron cultures to address the following Aims: to determine 1) if receptors for FGFs are expressed in a time-specific manner during development, 2) if FGFs alter GnRH progenitor cell expansion and the emergence of GnRH neurons, 3) if FGFs alter the migration of GnRH neurons into the forebrain, 4) if FGFs promote GnRH axon targeting, and 5) if IGF-I acts independently or synergistically with FGFs to promote the survival of GnRH neurons. Together, results from these Aims will provide important clues regarding how a neuroendocrine system critical for vertebrate reproduction develops and matures with the guidance of neurotrophic factors. Further, these results will aid in the understanding of cellular and molecular basis of developmental reproductive abnormalities that result from GnRH deficiency.