CYTOSKELETAL SIGNALING AND AXON GUIDANCE

描述（来自申请人的摘要）：建立和维护 细胞的形状和极性在多细胞的发育中起着关键作用。 有机体在发育中的神经系统中，神经元将轴突发送到它们的 正确的目标，以形成轴突支架， 建立了联系。在新生期，轴突是如何被引导到它们的目标的？ 神经系统？最近的努力表明，细胞外线索提供指导， 信息，并通过存在于生长物上的跨膜受体检测 视锥，位于延伸轴突末端的感觉运动结构。在 对这些线索的反应，生长锥的肌动蛋白细胞骨架， 介导生长锥运动，被改变以实现生长锥的定向迁移。 生长锥许多指导线索和他们的受体已经确定。少 已知的细胞内信号传导机制， 引导信号传递到肌动蛋白细胞骨架。本研究旨在 识别和表征连接轴突的细胞质信号传导机制 小杆线虫肌动蛋白细胞骨架的导向受体 优雅unc-115基因的突变导致特定的轴突导向， 成长的错误unc-115编码一种新的保守肌动蛋白结合蛋白， 可能调节肌动蛋白细胞骨架响应轴突的指导信号。 Unc-115在遗传上与Rac GT3信号传导作用，并在物理上相互作用 与新的WD-40重复蛋白AXM-1在轴突导向。三个C。 线虫Rac基因ced-10、mig-2和rac-2定义了三个平行和冗余的 介导轴突引导的信号通路。unc-115在rac-2中起作用 途径并与MIG-2和CED-10平行。很可能，115调节了 生长锥肌动蛋白细胞骨架响应于通过 RAC-2信令和AXM-1。这里描述的实验旨在阐明 unc-115在轴突导向信号转导中的作用。第一个目标是确定 其他基因通过两种方式与unc-115一起作用于轴突引导：筛选 与UNC-115相互作用的现有候选突变体;以及利用 Rac基因功能的冗余以筛选unc-115中的新突变体 通过合成的轴突缺陷与MIG-2的途径。第二个目标是 表征与所述β-115分子物理相互作用的分子， 包括AXM-1第三个目的是研究其分子机制， UNC-115功能是阐明在向 生长锥中的细胞骨架。

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.