EXTRACELLULAR MATRIX AND AXONAL GUIDANCE IN C ELEGANS

线虫的细胞外基质和轴突引导

• 批准号: 2703040
• 负责人: WILLIAM G WADSWORTH
• 金额: $ 19.8万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2703040
• 关键词: Caenorhabditis elegans; chimeric proteins; complementary DNA; developmental neurobiology; extracellular matrix proteins; gene mutation; genetic promoter element; genetically modified animals; immunocytochemistry; immunoelectron microscopy; in situ hybridization; neuroanatomy; neuronal guidance; nucleic acid sequence; site directed mutagenesis

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.

细胞在复杂组织的开发过程中迁移到新位置。 为了 例如，在神经系统的发展过程中，开创性轴突 迁移到特定的目标站点。 这种导航方式是如何的 成就是发育神经生物学的核心问题。 了解这一过程可能会导致治疗神经的新方法 受伤损害和疾病的新疗法受损的区域受损 神经元建立正确的突触连接的能力。 现在有几个重要的发展允许研究移民指导 在分子水平。 UNC-6，一种在秀丽隐杆线虫和网状蛋白中发现的蛋白质， 新发现的UNC-6的脊椎动物同源物是第一个分子 已知具有明确定义的作用为指导线索。 这些蛋白质是 开发中适当的圆周轴突迁移所必需的 线虫和脊椎动物的神经系统。 他们可能很重要 在其他迁移中也起作用。 我们的目标是了解如何 6/Netrin能够引导轴突和细胞迁移。 我们的研究会 采用强大的遗传和分子技术可用。 秀丽隐杆线以研究发展和功能。 由于UNC-6成员 家庭不仅在结构上保守，而且似乎非常明显 同样保守的功能，我们的研究也应该对 不断增长的研究领域。 UNC-6是层粘连蛋白相关的细胞外基质蛋白，需要 用于表皮基底表面的背侧和腹侧迁移。 作为一个简单的假设，UNC-6是一个分泌的矩阵指导提示 由在迁移细胞表面表达的受体跟踪。 一 已知受体（UNC-5）是背迁移所必需的。 这个模型 提供了研究结构布置和生物学的基础 构成该指导系统的各个组件的属性。 本提案中解决的主要问题包括：哪些细胞分泌 UNC-6及其如何分布在上皮上？ 什么受体（在 除了UNC-5）与UNC-6相互作用吗？ 其他哪些细胞外基质 蛋白质与UNC-6相互作用？ 这些相互作用的本质是什么。 这些问题的答案将为理解提供框架 形成紧张的一些最基本的过程 系统。