Fibroblast Growth Factor Regulation of Gonadotropin-Releasing Hormone Neurons

成纤维细胞生长因子对促性腺激素释放激素神经元的调节

• 批准号: 7151469
• 负责人: Pei-San Tsai
• 金额: $ 18.72万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151469
• 关键词: Address; Automobile Driving; Axon; Birth; Cells; Complex; Destinations; Development; Event; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptor 1; Fibroblast Growth Factor Receptors; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Growth Factor; Hormones; Insulin-Like Growth Factor I; Knowledge; Maintenance; Mitotic Activity; Molecular; Movement; Neuraxis; Neurons; Neurosecretory Systems; Nose; Phase; Physiology; Play; Production; Prosencephalon; Proteins; Regulation; Reproduction; Research; Role; Signal Transduction; Signaling Molecule; Staging; Stem cells; System; Time; Transgenic Model; Vertebrates; base; hormone deficiency; human FGF3 protein; insight; median eminence; migration; neurotrophic factor; proto-oncogene protein kfgf; reproductive; reproductive function

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.

描述(申请人提供)：促性腺激素释放激素(GnRH)神经元是启动和维持不同脊椎动物生殖功能的中心。在发育过程中，促性腺激素释放激素神经元进入连续的阶段，成熟为一个功能网络，能够支持成年后的生殖。这些阶段包括嗅觉安慰剂中细胞命运的指定，迁移到前脑，以及将轴突定位到中间隆起以释放激素。触发GnRH神经元进入这些阶段的信号以及调控每个阶段成熟的因素在很大程度上仍不清楚。我们假设神经营养因子提供时间特定的信号来驱动GnRH神经元的发育。在这个提案中，我们将使用一种候选神经营养因子的方法，并重点关注一类生长因子的作用，这些生长因子被证明在培养的原代和永生化的GnRH神经元中具有深刻的神经营养活性：成纤维细胞生长因子(FGFs)。此外，胰岛素样生长因子I(IGF-I)的作用将被研究，IGF-I是一种神经营养因子，以前被证明与FGF-2独立和/或协同作用。这一建议将利用现有的转基因模型和原代GnRH神经元培养相结合的方法来解决以下目标：1)FGFs受体在发育过程中是否以特定时间的方式表达，2)FGFs是否改变GnRH前体细胞的扩张和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轴突的靶向，以及5)IGF-I是否与FGFs单独或协同作用来促进GnRH神经元的存活。总之，这些目标的结果将为了解对脊椎动物繁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展和成熟提供重要线索。此外，这些结果将有助于理解由GnRH缺乏引起的发育生殖异常的细胞和分子基础。