Cytoskeletal Signaling and Axon Guidance

描述（由申请人提供）：在发育中的神经系统中，神经元必须将轴突延伸到其正确的靶点，以形成轴突支架，在该支架上进行功能性神经元连接。轴突末端的迁移生长锥感知并响应引导信息。这些研究的目的是使用C。elegans了解细胞骨架的信号网络，连接轴突的指导信号的变化，生长锥形态和通过肌动蛋白细胞骨架生长。在这个建议中，遗传，分子和在体内的时间推移生长锥成像方法将被用来解剖生长锥形态和生长的细胞骨架信号通路的作用。许多途径和分子已被确定影响轴突寻路。这些实验超越了“逐个基因”的方法来研究轴突寻路，而是旨在了解分子如何在通路和网络中相互关联，以控制轴突寻路和生长锥形态。第一个目的测试CDC-42在轴突寻路中作用于Rac GTP酶上游的想法。第二个目标集中于CDC-42下游的TIAM-1/静物Rac GTP交换因子（GEF）对Rac GTP酶的控制。目的2还被设计为测试Cdc 42 GEF UIG-1/Clg和EXC-5/Fgd 1在轴突寻路中对CDC-42的调节的作用。第三个目的是探测活化C激酶的NIK-15激酶和RACK-1/受体的作用以及它们在Rac非依赖性途径中与CDC-42下游的NIK- 115/abLIM的相互作用。第四个目标整合了前三个，是表征这些途径对生长锥丝状伪足的形成和生长过程中的形态的影响。这些实验的结果将显着有助于理解的细胞骨架信号网络参与生长锥形态的目标，并将开始，以解决这些不同的途径在轴突发育的细胞作用。 公共卫生相关性：轴突生长对神经系统发育和功能至关重要。本研究的目的是了解轴突生长的基本分子机制，这将为中枢神经系统损伤和中风以及发育性智力障碍后轴突再生的潜力提供深入了解。

DESCRIPTION (provided by applicant): In the developing nervous system, neurons must extend axons to their correct targets to form an axon scaffold upon which functional neuronal connections are made. The migrating growth cone at the distal axon tip senses and responds to guidance information. The aim of these studies is to use C. elegans to understand the cytoskeletal signaling networks that link axon guidance signals to changes in growth cone morphology and outgrowth via the actin cytoskeleton. In this proposal, genetic, molecular, and in vivo time-lapse growth cone imaging approaches will be used to dissect the roles of cytoskeletal signaling pathways in growth cone morphology and outgrowth. Many pathways and molecules have been identified that affect axon pathfinding. These experiments move beyond the "gene by gene" approach to studying axon pathfinding and instead are designed to understand how molecules relate to one another in pathways and networks to control axon pathfinding and growth cone morphology. The first aim tests the idea that CDC-42 acts upstream of Rac GTPases in axon pathfinding. The second aim focuses on the control of Rac GTPases by the TIAM-1/Still life Rac GTP exchange factor (GEF) downstream of CDC-42. Aim 2 also is designed to test the role of the Cdc42 GEFs UIG-1/Clg and EXC-5/Fgd1 on regulation of CDC-42 in axon pathfinding. The third aim is to probe the role of the MIG-15 NIK kinase and RACK-1/Receptor for activated C kinase and their interaction with UNC- 115/abLIM downstream of CDC-42 in a Rac-independent pathway. The fourth aim integrates the first three and is to characterize the effects of these pathways on growth cone filopodia formation and morphology during outgrowth. The results of these experiments will significantly contribute to the goal of understanding the cytoskeletal signaling networks involved in growth cone morphology and will begin to address the cellular roles of these distinct pathways in axon development. PUBLIC HEALTH RELEVANCE: Axon outgrowth is central to nervous system development and function. The goal of this proposal is to understand the basic molecular mechanisms of axon outgrowth, which will provide insight into the potential of axon regeneration after central nervous system injury and stroke as well as developmental mental retardation disorders.