FGF Regulation of GnRH Neurons

描述（由申请人提供）：促性腺激素释放激素（GnRH）神经元在多种脊椎动物生殖功能的启动和维持中起着核心作用。在发育过程中，GnRH神经元进入连续的阶段，成熟为能够支持成年期生殖的功能网络。这些阶段包括嗅觉基板中的细胞命运规范，向前脑的迁移，以及轴突向中隆起释放激素的目标。触发GnRH神经元进入这些阶段的信号，以及在每个阶段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。在本提案中，我们将使用候选神经营养因子方法，并将重点放在一系列生长因子的作用上，这些生长因子在培养的原代和永生化GnRH神经元中具有深远的神经营养活性：成纤维细胞生长因子（FGFs）。此外，将研究胰岛素样生长因子I （IGF-I）的作用，IGF-I是一种神经营养因子，以前被证明是独立和/或与FGF-2协同作用的。本提案将利用现有转基因模型和原代GnRH神经元培养的组合来解决以下目标：确定1)FGFs受体在发育过程中是否以时间特异性方式表达，2)FGFs是否改变GnRH祖细胞的扩增和GnRH神经元的出现，3)FGFs是否改变GnRH神经元向前脑的迁移，4)FGFs是否促进GnRH轴突靶向，以及5)IGF-I是否单独或协同作用于FGFs以促进GnRH神经元的存活。总之，这些目标的结果将为脊椎动物生殖至关重要的神经内分泌系统如何在神经营养因子的指导下发育和成熟提供重要线索。此外，这些结果将有助于理解由GnRH缺乏引起的发育性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.