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（GnRH，也称为 LHRH）的分泌对于调节垂体-性腺轴和确保几乎所有脊椎动物的生殖能力至关重要。 在胚胎和出生后早期发育过程中，GnRH 神经元从嗅板穿过筛板和嗅球迁移到前脑和下丘脑。 GnRH 神经元迁移的途径由起源于犁鼻器 (VNO) 的轴突组成，并从嗅球直接投射到前脑前脑。 有几个不同的事件决定 GnRH 神经元的目的地。 本提案中的每一个目标都旨在回答涉及其中一个或多个事件的基本问题。 1. 尾侧 VNN 转向携带 GnRH 神经元的腹侧前脑。 目标 1 旨在了解 netrins 及其受体 DCC 和 Unc-5 在确定 GnRH 神经元最终目的地中的作用。 2. GnRH 神经元的命运由嗅基板发育成 VNO 时决定。 神经系统其他部分的细胞命运决定的分子线索包括音速刺猬和一系列相关的信号转导分子。目标 3 将 Shh 信号传导与 GnRH 神经元发育联系起来。实验旨在检查几种 Shh 表达改变的动物模型。 3. 当 GnRH 神经元开始沿着 VNN 迁移时，多种因素可能决定 GnRH 神经元的迁移能力。 目标 2 将 GABA 表达与细胞运动联系起来。 我们将使用切片培养系统与 GFP 转基因动物结合来分析单细胞的迁移。 4. GnRH 神经元穿过独特的分子区域，包括鼻中隔的细胞外基质、筛板和前脑。 它们与环境的关系可能是通过许多细胞表面糖缀合物和细胞外基质分子（例如层粘连蛋白）介导的。 目标 1 和 4 将细胞表面和基质分子与迁移行为联系起来。 总体目标是确定定向 GnRH 神经元迁移的分子基础。 卡尔曼综合征和与Shh功能相关的综合征（Smith-Lemli-Opitz和基底细胞痣）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育的基本机制。