Cells in a developing embryo and in normal adult tissues send signals to each other to coordinate the differentiation, proliferation, and movement of cells. Not only do the signals have to be correct; they also must be perfectly coordinated. Otherwise, disasters like cancer can result. To explore the mechanisms of cell communication in a multicellular organism, we have turned to the fruit fly, Drosophila melanogaster. As a model system, Drosophila offers both complex patterns of the mammals and powerful methods for genetic analysis. More importantly, the signal transduction mechanisms between the fly and the mammals are remarkably similar. Our group is currently focusing on two key signal transduction pathways: the Drosophila JNK/JUN and JAK STAT signal transduction pathways. The Drosophila JNK/JUN pathway regulates epithelial cells sheet movement during embryogenesis and imaginal disc formation. Studies on the JNK/JUN-regulated cell movement may shed light on cell migration and tumor metastasis in mammals. The Drosophila JAK/STAT pathway regulates cell differentiation and cell fate determination in the developing fly. Hyperactivation of this pathway leads to melanotic tumor formation in larvae and the adult fly, due to cell fate misdetermination in the imaginal discs. The JAK/STAT system provides an excellent genetic model to study cell fate determination in development and tumor formation. Critical to our understanding the signal transduction mechanisms is the identification of all of the components that are involved in signal transmission. To achieve that goal, we have performed a P element-mediated gene disruption screen, examining over 50,000 mutant lines to identify genes that are essential to fly life. We recovered more than 2500 such mutants. Using a PCR-based sequencing protocol, we have sequenced the genomic DNA of all P insertion points. Taking advantage of the recently completed Drosophila genome sequence, we have identified the disrupted genes for most of the mutants. We are now doing a germline clone assay of the interesting genes to identify genes that function in the JNK/JUN and JAK/STAT signal transduction pathways. So far, we have identified several new genes in the two signal transduction pathways. In addition, we also identified a number of genes that function in other signal transduction pathways and biological processes; they will be distributed to interested laboratories for in-depth studies. In the JNK/JUN pathway, we have characterized a multidomain protein in detail. It functions as a scaffold or hub molecule that brings kinases and transcription factors together for efficient signaling (manuscript submitted). In the JAK/STAT pathway, we are focusing on three most interesting genes. Two of them are cell surface molecules that may identify the missing receptors of the signal transduction pathway. The third one is a molecule that connects the pathway to cell cycle regulation. These results will be published shortly. In the coming year, we will continue to examine in detail the functions of several of these genes. Meanwhile, in our P element screen we isolated several genes that are the fly homologues of human disease genes. We will carefully examine the disease-related genes' functions in the Drosophila model system.
