FGF Regulation of GnRH Neurons

FGF 对 GnRH 神经元的调节

• 批准号: 6832808
• 负责人: Pei-San Tsai
• 金额: $ 19.73万
• 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 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6832808
• 关键词: axon; cell migration; fibroblast growth factor; genetically modified animals; gonadotropin releasing factor; growth factor receptors; in situ hybridization; insulinlike growth factor; laboratory mouse; neuroendocrine system; neurogenesis; neuronal guidance; neurons; neuroregulation; neurotrophic factors; receptor expression; tissue /cell culture

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（由申请人提供）：促性腺激素释放激素（GnRH）神经元对于多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期繁殖的功能网络。这些阶段包括嗅觉基板中的细胞命运规范、迁移到前脑以及将轴突瞄准正中隆起以释放激素。触发 GnRH 神经元进入这些阶段的信号，以及每个阶段内调节成熟的因素仍然很大程度上未知。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，重点关注在培养的原代和永生化 GnRH 神经元中显示出具有深远神经营养活性的生长因子家族的作用：成纤维细胞生长因子 (FGF)。此外，还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，之前已显示其独立作用和/或与 FGF-2 协同作用。该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来解决以下目标：确定 1) FGF 受体在发育过程中是否以特定时间的方式表达，2) FGF 是否改变 GnRH 祖细胞扩张和 GnRH 神经元的出现，3) FGF 是否改变 GnRH 神经元向前脑的迁移，4) 是否 FGF 促进 GnRH 轴突靶向，5) IGF-I 是否独立或与 FGF 协同作用以促进 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育和成熟提供重要线索。此外，这些结果将有助于理解 GnRH 缺乏导致的发育生殖异常的细胞和分子基础。