MECHANISMS OF GNRH NEURON MIGRATION DURING DEVELOPMENT

发育过程中 GNRH 神经元迁移的机制

• 批准号: 2025714
• 负责人: GERALD A SCHWARTING
• 金额: $ 26.65万
• 依托单位: EUNICE KENNEDY SHRIVER CTR MTL RETARDATN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2025714
• 关键词: axon; cell adhesion molecules; cell migration; complementary DNA; developmental neurobiology; gamma aminobutyrate; genetic promoter element; genetically modified animals; gonadotropin releasing factor; green fluorescent proteins; laboratory mouse; neuronal guidance; neurons; olfactory nerve; prosencephalon; recombinant proteins; tissue /cell culture; video microscopy; vomeronasal systems

The secretion of gonadotropin-releasing hormone (GnRH) is critical for regulating the pituitary-gonadal axis and ensuring reproductive competence for virtually all vertebrates. GnRH neurons migrate from the olfactory placode across the cribriform plate and olfactory bulb, into the forebrain and hypothalamus during embryonic and early postnatal development. The majority of GnRH neurons migrate along the VNN through the nasal cavity. GnRH neurons then leave the main VNN and follow a small group of axons directly into the brain. We have recently identified the migratory track as a subset of the vomeronasal nerve. Preliminary studies suggest that 3 events play a role in the regulation of GnRH migration: i) GnRH neurons interact specifically with ligands on the migratory pathway; and ii) a group of co-migrating GABAergic neurons modulates the migration of GnRH neurons , and iii) selective axon branching and guidance of the caudal VNN establishes a chemically unique track for GnRH neurons. Our objective is to determine the molecular basis of directed GnRH neuron migration. Perturbation studies with enzymes, peptides, ligands, proteins and antibodies using in vitro slice cultures of the nose and forebrain, and in vivo will define the factors that regulate movement along the known route of GnRH cell migration. We will develop an in vivo marker for GnRH neurons in transgenic mice using transgenes containing the human GnRH promoter fused to green fluorescent protein cDNA. Green fluorescent protein (GFP)containing transgenic GnRH cells fluoresce when exposed to 395- 470nm light, and are thus identifiable microscopically in living tissue. GFP transgenic mice, in conjunction with slice cultures will allow us to test hypotheses that GnRH neurons use caudal branches of the VNN as guides for migration into the forebrain. The developmental relationship of the olfactory system and the forebrain is clinically significant. X-linked Kallmann syndrome is caused by a defect in the development of the olfactory system. This syndrome is characterized primarily by the inability to smell, anosmia; and abnormal development of the gonads, hypogonadotrophic hypogonadism. it has also been associated with numerous other neurological problems, including mental retardation. Results from these studies will aid our understanding of the development of the nervous system.

促性腺激素释放激素（GnRH）的分泌对于 调节垂体-性腺轴并确保生殖 几乎所有脊椎动物的能力。 GnRH 神经元从 嗅板穿过筛板和嗅球，进入 胚胎期和产后早期的前脑和下丘脑 发展。大多数 GnRH 神经元沿着 VNN 迁移 鼻腔。 GnRH 神经元然后离开主 VNN 并遵循 小群轴突直接进入大脑。我们最近有 确定迁移轨迹是犁鼻神经的一个子集。 初步研究表明，3个事件在调节中发挥作用 GnRH 迁移的过程：i) GnRH 神经元与配体特异性相互作用 在迁徙路径上； ii) 一组共同迁移的 GABAergic 神经元调节 GnRH 神经元的迁移，以及 iii) 选择性 轴突分支和尾部 VNN 的引导建立了化学 GnRH 神经元的独特轨迹。我们的目标是确定 定向 GnRH 神经元迁移的分子基础。扰动研究 与酶、肽、配体、蛋白质和抗体一起在体外使用 鼻子和前脑的切片培养物，在体内将定义 调节 GnRH 细胞沿已知路径运动的因素 迁移。我们将开发 GnRH 神经元的体内标记物 使用含有人 GnRH 启动子的转基因的转基因小鼠 与绿色荧光蛋白 cDNA 融合。绿色荧光蛋白 395- 含有 GFP 的转基因 GnRH 细胞会发出荧光 470nm 光，因此可以在活体中通过显微镜识别 组织。 GFP 转基因小鼠与切片培养物结合将 让我们能够检验 GnRH 神经元使用尾部分支的假设 VNN 作为迁移到前脑的指南。发展性的 临床上嗅觉系统与前脑的关系 重要的。 X连锁卡尔曼综合征是由X连锁缺陷引起的 嗅觉系统的发育。该综合征的特点是 主要是无法嗅觉、嗅觉丧失；以及发育异常 性腺，低促性腺激素性性腺功能减退症。它也曾被 与许多其他神经系统问题有关，包括精神问题 迟缓。这些研究的结果将有助于我们理解 神经系统的发育。