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 调节垂体-性腺轴，确保生殖 几乎所有脊椎动物的能力。促性腺激素释放激素神经元从 嗅觉定位穿过筛板和嗅球，进入 胚胎和出生后早期的前脑和下丘脑 发展。大多数促性腺激素释放激素神经元通过 鼻腔。然后，GnRH神经元离开主要的VNN，跟随 一小群轴突直接进入大脑。我们最近做了 确定了迁徙轨迹是犁鼻神经的一个子集。 初步研究表明，有3个事件在调节中发挥作用 促性腺激素释放激素迁移：I)促性腺激素释放激素神经元与配体特异性相互作用 关于迁徙途径；II)一群共同迁徙的GABA能 神经元调节GnRH神经元的迁移，以及III)选择性 轴突分支和尾侧迷走神经的引导在化学上建立了 GnRH神经元的独特轨迹。我们的目标是确定 促性腺激素释放激素神经元定向迁移的分子基础。摄动研究 与酶、多肽、配体、蛋白质和抗体在体外使用 鼻部和前脑的切片培养，在体内将定义 调节促性腺激素释放激素细胞已知路线运动的因子 迁移。我们将开发一种体内GnRH神经元标记物 利用含有人促性腺激素释放激素启动子的转基因小鼠 与绿色荧光蛋白基因融合。绿色荧光蛋白 (GFP)转基因GnRH细胞在395- 470 nm的光线，因此在显微镜下可以在生活中识别 组织。GFP转基因小鼠，结合切片培养将 允许我们测试假设GnRH神经元使用尾侧支 迷走神经作为迁移到前脑的向导。发展中的 嗅觉系统与前脑的临床关系 意义重大。X-连锁Kallmann综合征是由 嗅觉系统的发展。这种综合征的特点是 主要由嗅觉障碍、嗅觉障碍和发育异常引起 性腺功能低下，性腺功能减退。它也一直是 与许多其他神经问题有关，包括精神疾病 智力迟缓。这些研究的结果将有助于我们理解 神经系统的发育。