Molecular Genetic Characterization of Mutationally-Induced Cell Death in C. Elegans

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Dominant mutations in two C. elegans genes, mec-4 and deg-1, induce the deaths of specific groups of neurons. Dying neurons are characterized by cell swelling and morphologically resemble a commonly observed pattern of death termed necrosis. Because in C. elegans cell death mechanisms can be dissected using genetic approaches characterization of this necrotic like death should provide novel insight into this death process. Mec-4 and deg-1 are members of a gene family that appear to encode membrane proteins. These genes (called degenerin genes) mutate in the same way to induce death. mec-4 and deg-1 DNA sequences appear to cross hybridize to DNAs from a number of species, raising the possibility that members of gene degenerin families in other organisms might also be capable of mutation to forms that induce death. The term long objective of the research is to determine how mec-4 (d) induced cell death occurs at the molecular level and to investigate whether similar death mechanisms are utilized in other cell types and in other organisms. Specifically, the work outlined in this proposal will 1) accomplish a structure/function analysis to define domains and amino acids required for mec-4 function, 2) identify suppressor mutations that block mec-4(d)-induced death to identify proteins that participate in the death process, and 3) isolate degenerin family members from different species. %%% Elucidation of mechanisms of cell death are important for understanding development, homeostasis and pathology.