Signaling pathways that regulate cytoskeletal dynamics in Caenorhabditis elegans

人体的骨骼、软骨、肌肉和肌腱为个体提供灵活性和运动性。在细胞水平上，细胞骨架通过协调各种细胞形状的变化和运动来执行相同的功能，包括细胞分裂、细胞迁移、细胞生长和细胞内运输。但是，是什么调节了细胞骨架的动态，这种变化是如何启动的呢？本研究方案就是为了回答这些问题。具体地说，我们专注于阐明遗传途径和细胞机制，这些遗传途径和细胞机制允许外部信号中包含的信息被细胞同化，并传递到细胞骨架，以引起细胞形状的变化。我们过去的研究确定了UNC-53和导航器(NAV)，这是在蠕虫和人类中发现的一个蛋白质家族，调节细胞的迁移、发育过程中神经元和细胞过程的生长，以及细胞生命周期中分子的持续运输。随后对新的分子相互作用的表征和对细胞迁移和生长的实时成像研究表明，NAV在细胞骨架组装点发挥其活性。但是是什么指导UNC-53/NAV做到这一点呢？目前的提案中概述了两个主要的研究方向：第一，确定调节细胞内UNC-53/NAV活性的外部信号和细胞表面受体；第二，了解UNC-53/NAV在细胞内转运中的功能。Wnt家族的信号分子是UNC-53的优秀候选激活剂。Wnt基因的突变会产生与UNC-53突变体类似的缺陷。使用遗传学、分子生物学和各种视觉记者作为工具来突出特定的细胞类型，目前的研究旨在确定UNC-53的活性是否依赖于Wnt信号。由于Navigator和Wnt信号成分在自然界中都是高度保守的，因此所获得的结果很可能与我们对多细胞生物体中一些最基本的生理过程背后的分子机制的理解有关(例如，神经细胞如何长出延伸很长距离的轴突)。通过这项研究计划，几名研究生和本科生将接受遗传学、分子生物学、转基因和高分辨率显微镜技术方面的高级培训，为他们作为学术界或生物技术行业研究人员的未来职业生涯做好准备。**

The bones, cartilage, muscles and tendons of the human body provide flexibility and movement to the individual. At the cellular level, the cytoskeleton performs an equivalent function, by orchestrating a variety of cellular shape changes and movements, including cell division, cell migration, cell outgrowth, and intracellular transport. But what regulates cytoskeleton dynamics and how is this change initiated? This research proposal is aimed at answering these questions. Specifically, we are focused at elucidating the genetic pathways and cellular mechanisms that allows the information contained in an external signal to be assimilated by the cell and relayed to the cytoskeleton to invoke cell shape changes. Our past research identified UNC-53 and the Navigators (NAVs), a family of proteins found in both worms and humans that regulate the migration of cells, the outgrowth of neuronal and cellular processes during development, and the ongoing transport of molecules in the cell during its lifetime. The subsequent characterization of novel molecular interactions and live imaging studies of cell migrations and outgrowth have suggested that NAVs exert their activity at the point of cytoskeleton assembly. But what instructs UNC-53/NAVs to do this?  There are two main thrusts of the research outlined in the current proposal: firstly, to identify the external signals and cell surface receptors that regulate UNC-53/NAV activity inside the cell; and, secondly, to understand the function of UNC-53/NAVs in intracellular transport. The Wnt family of signaling molecules are excellent candidate UNC-53 activators. Mutations in Wnt genes generate similar defects observed in unc-53 mutants. Using genetics, molecular biology and a variety of visual reporters as tools to highlight specific cell types, the current research is aimed at determining whether or not UNC-53 activity is dependent on Wnt signaling. As both the Navigators and Wnt signaling components are highly conserved in nature, the results obtained are likely to be generally relevant to our understanding of the molecular mechanisms behind some of the most basic physiological processes in a multi-cellular organism (e.g. how a nerve cell can grow out axons that extend long distances). Through this research program, several graduate and undergraduate students will receive advanced training in genetics, molecular biology, transgenesis, and high resolution microscopy techniques, preparing them for ongoing careers as researchers in academia or in the biotechnology industry.**