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.
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