MECHANISMS OF GNRH NEURON MIGRATION DURING DEVELOPMENT

发育过程中 GNRH 神经元迁移的机制

• 批准号: 6401606
• 负责人: GERALD A SCHWARTING
• 金额: $ 9.62万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 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 2001-07-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6401606
• 关键词: biological signal transduction; cell cell interaction; cell differentiation; cell migration; developmental neurobiology; extracellular matrix proteins; gamma aminobutyrate; genetically modified animals; gonadotropin releasing factor; laboratory mouse; mammalian embryology; neuronal guidance; neurons; neurotrophic factors; tissue /cell culture; vomeronasal systems

The secretion of gonadotropin-releasing hormone (GnRH, also called LHRH) 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 pathway that GnRH neurons migrate upon consists of axons that originate in the vomeronasal organ (VNO), and project beyond the olfactory bulb directly into the rostral forebrain. There are several distinct events that determine the destination of GnRH neurons. Each of the aims in this proposal is designed to answer fundamental questions involving one or more of these events. 1. The caudal VNN makes a turn to the ventral forebrain carrying GnRH neurons with it. Aim 1 is designed to understand the role of netrins and their receptors DCC and Unc-5 in determining the ultimate destination of GnRH neurons. 2. GnRH neuron fate is determined within the olfactory placode as it develops into the VNO. Molecular cues for cell fate determination in other parts of the nervous system include Sonic hedgehog and a cast of associated signal transduction molecules. Aim 3 relates Shh signaling to GnRH neuron development. Experiments are designed to examine several animal models of altered Shh expression. 3. As GnRH neurons begin to migrate along the VNN, multiple factors likely determine the ability of GnRH neurons to migrate. Aim 2 relates GABA expression to cell motility. We will use a slice culture system in conjunction with GFP transgenic animals to analyze migration on a single cell basis. 4. GnRH neurons make their way across a unique molecular terrain that includes the extracellular matrix of the nasal septum, the cribriform plate and the forebrain. Their relationship to the environment is likely mediated through a number of cell surface glycoconjugates and extracellular matrix molecules such as laminin. Aims 1 and 4 relate cell surface and matrix molecules to migratory behavior. The overall objective is to determine the molecular basis of directed GnRH neuron migration. Kallmann syndrome and syndromes related to Shh function (Smith-Lemli-Opitz and basal cell nevus) are associated with numerous neurological problems involving the structure and function of the olfactory system and forebrain. Results from these studies will aid in our understanding of fundamental mechanisms in nervous system development.

促性腺激素释放激素的分泌（GNRH，也称为LHRH）对于调节垂体 - 性 - 性 - 性轴和确保几乎所有脊椎动物的生殖能力至关重要。 GnRH神经元从遍布片状板和嗅球的嗅觉片段迁移到胚胎和早期产后发育期间的前脑和下丘脑。 GnRH神经元迁移的途径由轴突组成的轴突组成，该轴突源自源自沃梅纳纳斯器官（VNO），并直接超出嗅球超出嗅球前脑前脑。 有几个不同的事件决定了GNRH神经元的目的地。 该提案中的每个目标旨在回答涉及其中一个或多个事件的基本问题。 1。尾vnn转向带有gnRH神经元的腹前脑。 AIM 1旨在了解Netrins及其受体DCC和UNC-5在确定GNRH神经元的最终目的地中的作用。 2。GnRH神经元命运在嗅觉斑点内确定在VNO中。 神经系统其他部位的细胞命运测定的分子提示包括声音刺猬和相关信号转导分子。 AIM 3将SHH信号与GNRH神经元发育相关。实验旨在检查几种改变SHH表达的动物模型。 3。随着GNRH神经元开始沿VNN迁移，多个因素可能决定了GnRH神经元迁移的能力。 AIM 2将GABA表达与细胞运动有关。 我们将使用切片培养系统与GFP转基因动物一起以单个细胞为基础分析迁移。 4。GNRH神经元穿越独特的分子地形，其中包括鼻中隔的细胞外基质，曲折板和前脑。 它们与环境的关系很可能是通过许多细胞表面糖缀合物和细胞外基质分子（如层粘连蛋白）介导的。 目标1和4将细胞表面和基质分子与迁移行为相关联。 总体目标是确定定向GNRH神经元迁移的分子基础。 Kallmann综合征和与SHH功能有关的综合征（Smith-Lemli-Opitz和基底细胞奈夫）与涉及嗅觉系统和前脑的结构和功能的许多神经系统问题有关。 这些研究的结果将有助于我们理解神经系统发展中的基本机制。