MUTANT SCREENS FOR DEVELOPMENTALLY INTERACTING GENES

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Understanding embryonic development depends critically on learning how cells acquire their fates. Cancers can cause cells to take on aspects of two different fates, thus, learning the mechanisms underlying cell fate specification may lead to therapies for this devastating disease. Screens in model genetic organisms for mutations that suppress or enhance the phenotype of a known mutation have significantly augmented our understanding of how interesting gene networks affect cell fate; such screens have not yet been undertaken in vertebrates. This application proposes to use an existing model genetic organism, the nematode worm, Caenorhabditis elegans to design enhancer/suppressor screens that can then be applied to a new vertebrate genetic organism, the zebrafish, Danio rerio. The zebrafish floating head mutation causes notochord cells to take on aspects of two different cell fates. The pie-1 mutation has a similar effect on a specific C elegans blastomer, P2. In both cases, the affected cells retain a normal early signaling ability but then differentiate into a completely different cell type. The C elegans mom-2 mutation is partially penetrant and the mom-2 gene may encode the P2 signal. Worms carrying the mom-2 mutation will be mutagenized and screened for new mutations that enhance or suppress the mom-2 phenotype. The proposed experiments will provide new insights into cell fate specification in C. Elegans as well as providing experience designing and assessing such screens, as a prelude to sesigning similar screens for genes interacting during zebrafish development.