The proposed experiments are directed toward understanding the role of the armadillo gene of Drosophila in organizing cell-cell adhesive junctions, and in mediating transduction of the wingless intercellular signal. The convergence of research into pattern formation in Drosophila and into the biochemistry and cell biology of adhesive junctions in mammalian cells has led to the development of a model for the role of adhesive junctions in development. Our experiments will test this model. Cell adhesion has been thought to play an important role both in normal development, and in the changes in cell behavior that occur during malignant transformation. The identification of the armadillo gene as the Drosophila homolog of plakoglobin and beta-catenin, molecules that are key components of different mammalian adhesive junctions, provides us with a genetic entrypoint into the function of these junctions. Only a few of the genes known to be involved in cell interactions in Drosophila have been molecularly characterized. The level of knowledge of the molecular nature of the armadillo gene product, and the tools which exist for studying it on a biochemical level, position us to move beyond the initial molecular analysis to examine the biochemistry and cell biology of armadillo protein.
The specific aims begin with determining whether armadillo protein associates with other proteins, as do its mammalian homologs. Biochemical and genetic approaches will be used to identify, and ultimately clone these armadillo -associated proteins. The nature of armadillo protein modification will be determined, and the role of other segment polarity genes in this modification examined. The function of armadillo will be explored by examining the function of mutant proteins both in Drosophila and in the heterologous mammalian tissue culture system. Finally, we will morphologically characterize intercellular adhesive junctions, and examine whether armadillo mutations disrupt their formation or structure.
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