EXTRACELLULAR MATRIX AND AXONAL GUIDANCE IN C ELEGANS

在复杂组织的发育过程中，细胞迁移到新的位置。为 例如，在神经系统的发育过程中，先驱轴突 迁移到特定的目标站点。这种类型的导航是如何 已完成一直是发育神经生物学的中心问题。 了解这一过程可能会导致治疗神经的新方法 损伤损伤的肌束和损伤疾病的新治疗方法 神经元建立正确突触连接的能力。 现在有几个重要的发展使人们能够研究迁徙指导 在分子水平上。在线虫和netrins中发现的一种蛋白质UNC-6， 新发现的脊椎动物UNC-6同源物是第一个分子 已知具有明确定义的作为指导线索的作用。这些蛋白质是 在发育过程中需要适当的周向轴突迁移 线虫和脊椎动物的神经系统。他们可能有重要的 在其他迁移中也起作用。我们的目标是了解北卡罗来纳大学如何- 6/netrin能够引导轴突和细胞迁移。我们的研究将 利用C. 研究雅致的发育和功能。因为北大西洋公约组织第六委员会的成员 家庭不仅在结构上保守，而且看起来非常 在功能上也是保守的，我们的研究应该对 不断发展的研究领域。 UNC-6是一种与层粘连蛋白相关的细胞外基质蛋白，是 用于表皮基面上的背侧和腹侧迁移。 作为一个简单的假设，UNC-6是一个秘密的矩阵指导线索，它是 通过迁移细胞表面表达的受体进行跟踪。一 受体(UNC-5)是已知的背部迁移所必需的。这款车 为研究结构安排和生物学行为提供了基础 组成该制导系统的各种组件的属性。 这项提案涉及的主要问题包括：哪些细胞分泌 UNC-6及其在上皮细胞中的分布情况？什么受体(在 除了UNC-5)与UNC-6交互？还有哪些细胞外基质 蛋白质与UNC-6相互作用？这些互动的性质是什么？ 对这些问题的回答将为理解 形成紧张情绪的一些最基本的过程 系统。

Cells migrate to new location during development of complex tissues. For example, during the development of the nervous system, pioneering axons migrate to specific target sites. How this type of navigation is accomplished has been a central issue in developmental neurobiology. Understanding this process could lead to new approaches to treat nerve tracts damaged by injuries and to new treatments for disorders which impair the ability of neurons to make correct synaptic connections. Several important developments now allow migrational guidance to be studied at the molecular level. UNC-6, a protein found in C. elegans, and netrins, the newly discovered vertebrate homologs of UNC-6, are the first molecules known to have a clearly defined role as guidance cues. These proteins are required for proper circumferential axon migrations in the developing nervous system of nematodes and vertebrates. They may have important functions in other migrations as well. Our goal is to understand how UNC- 6/netrin is able to guide axon and cell migrations. Our research will employ the powerful genetic and molecular techniques available in C. elegans to study development and function. Since members of the UNC-6 family are not only structurally conserved but appear to be remarkably conserved in function as well, our studies should have a broad impact on a growing field of study. UNC-6 is a laminin-related extracellular matrix protein which is required for dorsal and ventral migrations on the basal surface of the epidermis. As a simple hypothesis, UNC-6 is a secreted matrix guidance cue which is tracked by receptors expressed on the surface of migrating cells. One receptor (UNC-5) is known to be required for dorsal migrations. This model provides the basis to study structural arrangements and biological properties of the various components which comprise this guidance system. Major questions addressed in this proposal include: Which cells secrete UNC-6 and how is it distributed across the epithelium? What receptors (in addition to UNC-5) interact with UNC-6? What other extracellular matrix proteins interact with UNC-6? What are the nature of these interactions. The answers to these questions will provide the framework for understanding some of the most fundamental processes involved in forming the nervous system.