NEURONAL MIGRATION IN C ELEGANS

拟议研究的总体目标是调查 控制神经元迁移的调节机制。要理解这一点 过程中必须回答几个关键问题。神经元是如何决定 迁移？是什么定义了单个迁移神经元所走的路径？ 神经元如何知道它们已经到达了它们的最终目的地？我们的 解决这些问题的方法是对基因进行遗传/分子分析 参与秀丽隐杆线虫HSN神经元的迁移 产卵所需的一对5-羟色胺能运动神经元。一共有五个 对拟议的研究提出了具体的目标。(1)我们的初步目标是 通过突变确定HSN迁移所需的基因。建议数 基因筛查的设计是为了识别大多数HSN迁移基因， 包括对生存能力或生育能力至关重要的那些。(2)自上一次 突变筛选表明，HSN需要许多基因 迁移，将分析突变体的表型，以确定如何 这些基因在HSN的迁移中起作用。那些发挥关键作用的基因将 被给予最高的优先权。尤其是，我们将重点研究 多种细胞类型的迁移。(3)优先级最高的基因将 被克隆并测定它们的序列。序列分析可能揭示 基因产物的生化功能，然后可以直接测试。 (4)对于最优先基因，进行遗传嵌合分析和基因 表达研究将用于研究这些基因何时何地 功能。(5)EGL-43基因在HSN的迁移和转移中起关键作用。 包含与老鼠的锌指图案密切相关的锌指图案 EVI-1基因。我们的工作模型是Egl-43蛋白 转录调控其他在HSN中更直接发挥作用的基因 迁移。这一模型将通过确定Egl-43是否 蛋白质是一种序列特异的DNA结合蛋白。这些实验 也可能导致对Egl-43基因的生化鉴定 转录调控。 这种方法应该导致对如何具体地 神经元迁移。突变筛选应该识别出所需的大部分基因 用于HSN迁移。表型分析应该阐明它们所扮演的角色 不仅在HSN迁移中，而且在迁移和 其他细胞类型的发育。镶嵌分析与基因表达 研究应确定协调HSN的细胞相互作用 对相关基因的迁移和分子分析应该会揭示 这些互动的性质。

The overall objective of the proposed research is to investigate the regulatory mechanisms that control neuronal migration. To understand this process several key questions must be answered. How do neurons decide to migrate? What defines the pathways taken by individual migrating neurons? How do neurons know that they have reached their final destinations? Our approach to these questions is a genetic/molecular analysis of genes involved in the migrations of the Caenorhabditis elegans HSN neurons, a pair of serotonergic motor neurons required for egg laying. There are five specific aims to the proposed research. (1) Our initial goal is to identify by mutation genes required for HSN migration. The proposed genetic screens are designed to identify most HSN-migration genes, including those essential for viability or fertility. (2) Since previous mutant screens indicate that there are many genes required for HSN migration, the phenotypes of the mutants will be analyzed to determine how the genes function in HSN migration. Those genes that play key roles will be given top priority. In particular, we will focus on genes required for the migrations of multiple cell types. (3) The highest priority genes will be cloned and their sequences determined. Sequence analysis may reveal the biochemical function of a gene product, which can then be tested directly. (4) For the highest priority genes, genetic mosaic analysis and gene expression studies will be used to investigate when and where these genes function. (5) The egl-43 gene plays a key role in HSN migration and contains zinc-finger motifs that are closely related to those of the mouse Evi-1 gene. Our working model is that the Egl-43 protein transcriptionally regulates other genes that function more directly in HSN migration. This model will be tested directly by determining if the Egl-43 protein is a sequence-specific DNA binding protein. These experiments could also lead to the biochemical identification of genes that Egl-43 transcriptionally regulates. This approach should lead to a detailed understanding of how a specific neuron migrates. Mutant screens should identify most of the genes required for HSN migration. Phenotypic analysis should elucidate the roles played by the genes not only in HSN migration but also in the migration and development of other cell types. Mosaic analysis and gene expression studies should identify the cell interactions that coordinate HSN migration and molecular analysis of the genes involved should reveal the nature of these interactions.