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.

细胞在复杂组织的发育过程中迁移到新的位置。 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 这是发育神经生物学的一个中心问题。 了解这一过程可能会导致新的方法来治疗神经 以及用于损伤的疾病的新治疗方法， 神经元建立正确突触连接的能力。 几个重要的发展现在允许迁移指导进行研究 在分子水平上。 β-6蛋白是在C. elegans，and netrins netrins， 最新发现的脊椎动物中的β-6同源物是第一个 已知具有明确定义的引导线索的作用。 这些蛋白质 在发育过程中， 线虫和脊椎动物的神经系统。 他们可能有重要的 在其他的迁移中也是如此。 我们的目标是了解如何... 6/netrin能够引导轴突和细胞迁移。 我们的研究将 利用C. elegans来研究发育和功能。 自1966年以来， 家族不仅在结构上保守， 在功能上也是保守的，我们的研究应该对一个 不断增长的研究领域。 ICAM-6是一种层粘连蛋白相关的细胞外基质蛋白， 用于表皮基底表面上的背侧和腹侧迁移。 作为一个简单的假设，β 2 -6是一种分泌的基质引导因子， 由迁移细胞表面表达的受体追踪。 一 已知背侧迁移需要受体（β-5）。 该模型 为研究结构排列和生物学提供了基础 包括该制导系统的各种组件的特性。 该提案中涉及的主要问题包括：哪些细胞分泌 它是如何在上皮中分布的？ 什么受体（在 除了与α-5）与α-6相互作用？ 什么其他的细胞外基质 蛋白质与β-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 一些最基本的过程参与形成神经 系统