Approaches to studying axon fasciculation

描述（由申请人提供）：了解轴突如何找到它们的突触靶点是神经发育中的一个基本问题。虽然在阐明轴突引导机制方面取得了很大进展，但对轴突如何在神经束的特定区域内成束却知之甚少。我们建议在C. elegans与重点的HSN轴突。在整个神经系统建立后，HSN轴突沿着腹神经索延伸。HSN生长锥沿着沿着PVQ和PVP轴突成束，并且该项目的短期目标是确定限定HSN沿着其在神经束中的特定路径沿着的能力的线索。虽然很少有人知道哺乳动物神经内的轴突如何成束，最近的研究结果表明，神经内的嗅觉轴突的分类是重要的，在他们的目标在嗅球。HSN可能为哺乳动物中这些神经是如何组织的提供了一个模型。该提案有三个具体目标。在第一个目标中，将使用GRASP标记不同轴突之间的界面。在第二个目标中，将开发RNAi方法来鉴定参与HSN轴突成束的基因。这些方法应该绕过由必需基因的RNAi引起的致死效应和由其他轴突成束的早期缺陷引起的间接效应。在第三个目标中，将测试这些方法以阐明神经递质乙酰胆碱在轴突成束中的作用。 公共卫生相关性：了解这些轴突如何找到它们的目标是神经发育中的一个基本问题。虽然在阐明轴突引导机制方面取得了很大进展，但对轴突如何沿着神经束的特定区域沿着知之甚少。我们建议在C. elegans是一种模式生物，在定义轴突引导功能的保守分子方面发挥了重要作用。

DESCRIPTION (provided by applicant): Understanding how axons find their synaptic targets is a fundamental problem in neurodevelopment. While great progress has been made in elucidating the mechanisms of axon guidance, less is known about how axons fasciculate within specific regions of a nerve bundle. We propose to study this problem in C. elegans with a focus on the HSN axon. The HSN axon extends along the ventral nerve cord after the entire nervous system has been established. The HSN growth cone fasciculates along the PVQ and PVP axons, and the short-term goal of this project is to identify the cues that define the HSN's ability to grow along its specific path in the nerve bundle. While little is known about how axons fasciculate within mammalian nerves, recent findings suggest that sorting of olfactory axons within the nerve are important in their targeting at the olfactory bulb. The HSN may provide a model for how such nerves are organized in mammals. The proposal has three specific aims. In the first aim, the interface between the different axons will be labeled using GRASP. In the second aim, RNAi approaches to identify genes involved in HSN axon fasciculation will be developed. These approaches should bypass the lethal effects caused by RNAi of essential genes and indirect effects caused by earlier defects in the fasciculation of other axons. In the third aim, the approaches will be tested to elucidate the role of the neurotransmitter acetylcholine in axon fasciculation.. PUBLIC HEALTH RELEVANCE: Understanding how these axons find their targets is a fundamental problem in neurodevelopment. While great progress has been made in elucidating the mechanisms of axon guidance, less is known about how axons grow along specific regions of a nerve bundle. We propose to study this problem in C. elegans, a model organism that has been instrumental in defined conserved molecules that function axon guidance.