Signaling pathways controlling axon pathfinding

描述（申请人提供）：神经系统由大量神经元组成，通过轴突精确连接。这种复杂的轴突网络对所有行为功能都很重要，并且主要是在胚胎发生过程中在各种引导分子的控制下建立的。异常发育可能导致神经元连接错误，引起各种神经和精神障碍。长期目标是了解生长锥信号机制控制轴突的定向生长在建立神经回路。了解轴突寻路的分子机制可能为成人中枢神经系统损伤后的轴突再生提供重要的工具。轴突引导的一个融合主题是，经常发现多个信号通路在单个神经元中起作用，这就提出了一个基本问题，即信号通路如何整合到同一个生长锥中，生长锥是位于轴突尖端的细胞装置，负责感知引导信号和控制生长锥。分别发现了两个主要的化学驱避通路，即Semaphorin/Neuropilin通路和Slit/Robo通路。初步研究表明两种信号通路之间存在意想不到的串扰。本研究的目的是探索这两种主要化学驱避途径之间的串扰机制以及生长锥信号趋同的生物学意义。这项研究将有助于揭示轴突引导信号通路的组织，并进一步了解神经系统发育的分子机制。

DESCRIPTION (provided by applicant): The nervous system is made of a large number of neurons, precisely connected by axons. This complex axonal network is important to all behavioral functions and is established largely during embryogenesis under the control of a variety of guidance molecules. Abnormal development may lead to errors in neuronal connections, causing various neurological and mental disorders. The long-term objective is to understand the growth cone signaling mechanisms controlling directional growth of axons in building neural circuits. Understanding molecular mechanisms underlying axon pathfinding may provide crucial tools for axonal regeneration in the adult central nervous system following injury. A merging theme in axon guidance is that multiple signaling pathways are frequently found to function in one single neuron, raising a fundamental question of how the signaling pathways are integrated in the same growth cone, the cellular apparatus located at the tip of the axon responsible for sensing guidance cues and growth cone steering. Two major chemorepellent pathways, the Semaphorin/Neuropilin pathway and the Slit/Robo pathway, were discovered separately. Preliminary studies suggest an unexpected crosstalk between the two signaling pathways. The goal of the proposed research is to explore the mechanism of the crosstalk between these two major chemorepellent pathways and the biological significance of growth cone signaling convergence. The proposed study will shed light on the organization of axon guidance signaling pathways and further the understanding of molecular mechanisms of nervous system development .