Signaling pathways controlling axon pathfinding

描述(申请人提供)：神经系统由大量神经元组成，由轴突精确连接。这种复杂的轴突网络对所有的行为功能都很重要，并且主要是在胚胎发育过程中在各种引导分子的控制下建立的。发育异常可能导致神经元连接错误，导致各种神经和精神障碍。长期目标是了解在构建神经回路中控制轴突定向生长的生长锥信号机制。了解轴突寻路的分子机制可能为成年中枢神经系统损伤后轴突再生提供重要的工具。轴突引导的一个合并主题是，经常发现多个信号通路在一个神经元中发挥作用，这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，位于轴突顶端的细胞装置负责感知引导线索和生长锥引导。分别发现了Semaphorin/Neuropilin途径和Sit/Robo途径两条主要的化学排泄途径。初步研究表明，这两条信号通路之间存在意想不到的串扰。这项研究的目的是探索这两条主要的化学抑制途径之间的串扰机制以及生长激素信号融合的生物学意义。这项拟议的研究将有助于阐明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 .