The long-term objective of this proposal is the elucidation of the cellular, genetic and molecular mechanisms that control patterns of cell division and cell fate during development. Toward this end, genes involved in specific aspects of the development of the nematode Caenorhabditis elegans will be identified and characterized. Particular emphasis will be placed on the genetic analysis of the cell-cell interactions that control the cell lineages of C. elegans vulval development. The genetic pathway of vulval development is the most extensively defined pathway in C. elegans. New genes in this pathway will be sought by identifying mutations that result in novel classes of vulval abnormalities as well as mutations that either suppress or enhance the phenotypes caused by existing vulval developmental mutations. Certain non-vulval cell lineages also will be studied. To elucidate the nature and specificity of the action of particular genes that affect cell lineages, detailed genetic analyses will be performed. For example, both how existing mutations perturb gene activity and the """"""""null"""""""" (loss-of-function) phenotype of each gene will be determined. In addition, temperature-shift experiments will reveal the time(s) of gene action, and mosaic analyses will reveal the site(s) of gene action. Gene interactions will be analyzed to define genetic pathways. Genes that perturb programmed cell deaths also will be examined; both genes that affect the """"""""program"""""""" of programmed cell death and genes that specify which cells are to express this program will be sought and characterizes. Genes that control cell lineage and cell fate will be molecularly cloned and analyzed; these experiments should define developmental pathways at a molecular level and may elucidate the molecular bases of the specification of cell lineage and cell fate. The study of C. elegans cell lineage should reveal how cell division is normally controlled in a multicellular animal and how this control can be disrupted. Such knowledge may prove relevant to an understanding of the cellular proliferation that characterized cancerous growth. Knowledge of the mechanisms of programmed cell death and the ways in which mutations can perturb patterns of cell death may indicate the bases of human disorders involving abnormal cell deaths. In addition, a basic understanding of nematode biology should help in the prevention and treatment of diseases caused by parasitic nematodes, which are a major source of human suffering in the world today.
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