MECHANISMS OF GNRH NEURON MIGRATION DURING DEVELOPMENT

促性腺激素释放激素(GnRH，又称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都是至关重要的。在胚胎和出生后早期发育过程中，促性腺激素释放激素神经元从嗅觉平台穿过筛板和嗅球，迁移到前脑和下丘脑。促性腺激素释放激素神经元迁移的路径由起源于穹隆鼻器(VNO)的轴突组成，并从嗅球直接投射到前脑吻侧。有几个不同的事件决定了GnRH神经元的去向。本提案中的每个目标都旨在回答涉及一个或多个此类事件的基本问题。1.尾侧VNN转向腹侧前脑，携带GnRH神经元。目的1旨在了解Netrins及其受体DCC和UNC-5在决定GnRH神经元最终目的地中的作用。2.促性腺激素释放激素神经元在嗅觉定位体内发育为迷走神经时决定神经元的命运。神经系统其他部分决定细胞命运的分子线索包括Sonic hedgehog和一系列相关的信号转导分子。目的3将Shh信号与GnRH神经元发育联系起来。实验旨在检验几种Shh表达改变的动物模型。3.随着GnRH神经元开始沿VNN迁移，多种因素可能决定了GnRH神经元的迁移能力。目的2将GABA的表达与细胞运动联系起来。我们将使用切片培养系统结合GFP转基因动物来分析单细胞的迁移。4.促性腺激素释放激素神经元穿过一个独特的分子地形，包括鼻中隔、筛板和前脑的细胞外基质。它们与环境的关系可能是通过一些细胞表面糖结合物和细胞外基质分子，如层粘连蛋白来调节的。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GnRH神经元定向迁移的分子基础。Kallmann综合征和与Shh功能相关的综合征(Smith-Lemli-Opitz和基底细胞痣)与许多神经系统问题有关，涉及嗅觉系统和前脑的结构和功能。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。

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.