CYTOSKELETAL SIGNALING AND AXON GUIDANCE

细胞骨架信号传导和轴突引导

• 批准号: 6490989
• 负责人: Erik A Lundquist
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-18 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6490989
• 关键词: Caenorhabditis elegans; actins; axon; binding sites; biological signal transduction; cell cell interaction; cell component structure /function; cell membrane; cytoskeleton; fluorescence microscopy; gene expression; gene mutation; genetic library; genetic mapping; genetic regulation; genetic screening; growth cones; intermolecular interaction; molecular cloning; neuronal guidance; nucleic acid quantitation /detection

DESCRIPTION (From the Applicant's Abstract): The establishment and maintenance of cell shape and polarity play key roles in the development of multicellular organisms. In the developing nervous system, neurons send axons to their correct targets to form an axon scaffold upon which functional neuronal connections are made. How are axons guided to their targets in the nascent nervous system? Recent efforts suggest that extracellular cues provide guidance information and are detected by transmembrane receptors present on the growth cone, the sensory motile structure at the distal tip of an extending axon. In response to such cues, the actin cytoskeleton of the growth cone, which mediates growth cone movement, is altered to achieve directed migration of the growth cone. Many guidance cues and their receptors have been identified. Less is known about the intracellular signaling mechanisms that transmit axon guidance signals to the actin cytoskeleton. The study proposed here aims to identify and characterize cytoplasmic signaling mechanisms that link axon guidance receptors to the actin cytoskeleton in the nematode Caenorhabditis elegans. Mutations in the unc-115 gene cause specific axon guidance and outgrowth errors. Unc-115 encodes a new conserved actin-binding protein that might modulate the actin cytoskeleton in response to axon guidance signals. Unc-115 acts genetically with Rac GTPase signaling and interacts physically with the novel WD-40 repeat protein AXM-1 in axon guidance. The three C. elegans Rac genes, ced-10, mig-2 and rac-2, define three parallel and redundant signaling pathways that mediate axon guidance. Unc-115 acts in the rac-2 pathway and in parallel to mig-2 and ced-10. Possibly, UNC-115 modulates the growth cone actin cytoskeleton in response to guidance cues transmitted through RAC-2 signaling and AXM-1. Experiments described here aim to elucidate the role of unc-115 in axon guidance signal transduction. The first aim is to identify additional genes that act with unc-115 in axon guidance by two means: screening existing candidate mutants for interactions with unc-115; and utilizing the redundancy in Rac gene function to screen for new mutants in the unc-115 pathway by virtue of synthetic axon defects with mig-2. The second aim is to characterize molecules that interact physically with the UNC-115 molecule, including AXM-1. The third aim is to investigate the molecular mechanisms of unc-115 function to elucidate events taking place during signaling to the cytoskeleton in the growth cone.

描述（摘自申请人的摘要）：建立和维护 细胞形状和极性在多细胞发展中起关键作用 有机体。在发育中的神经系统中，神经元将轴突发送到其 正确的目标形成轴突支架，功能性神经元 建立了连接。如何将轴突引导到新生的目标 神经系统？最近的努力表明，细胞外提示提供指导 信息并由存在的跨膜受体检测到生长 锥，延伸轴突远端的感觉运动结构。在 对这种提示的反应，生长锥的肌动蛋白细胞骨架， 介导生长锥运动的变化以实现的定向迁移 生长锥。已经确定了许多指导提示及其受体。较少的 已经知道传输轴突的细胞内信号传导机制 肌动蛋白细胞骨架的引导信号。这里提出的研究旨在 识别和表征连接轴突的细胞质信号传导机制 线虫炎炎的肌动蛋白细胞骨架的引导受体 秀丽隐杆线。 UNC-115基因中的突变引起特定的轴突引导和 出现错误。 UNC-115编码一种新的保守肌动蛋白结合蛋白 可能会根据轴突引导信号调节肌动蛋白细胞骨架。 UNC-115用RAC GTPase信号传导遗传起作用，并在物理上相互作用 在轴突引导中，新型WD-40重复蛋白AXM-1。三个C 秀丽隐杆线RAC基因，CED-10，MIG-2和RAC-2，定义了三个平行和多余的 介导轴突引导的信号通路。 UNC-115在RAC-2中行动 途径并平行于MIG-2和CED-10。可能，UNC-115调节 生长锥肌动蛋白细胞骨架，以响应通过 RAC-2信号传导和AXM-1。此处描述的实验旨在阐明角色 轴突引导信号转导中的UNC-115。第一个目的是确定 通过两种方式在Axon指导中用UNC-115起作用的其他基因：筛选 与UNC-115相互作用的现有候选突变体；并利用 RAC基因功能的冗余以筛选UNC-115中的新突变体 通过MIG-2的合成轴突缺陷，途径。第二个目标是 表征与UNC-115分子物理相互作用的分子， 包括AXM-1。第三个目的是研究分子机制 UNC-115功能以阐明在发出信号期间发生的事件 生长锥中的细胞骨架。