The development of multicellular animals requires the coordinated activities of cell-cell signaling pathways and cell-type specific transcription factors. In this project, how these inputs are orchestrated during the development of animal appendages will be investigated. Using Drosophila melanogaster as the model system, the focus is how two signaling pathways, Wingless (Wg) and the BMP homolog Decapentaplegic (Dpp), create the proximo-distal (PD) axis of the leg. Previous work established that Wg and Dpp combine to activate the transcription of target genes at discreet positions along the PD axis. However, how these signals translate to transcriptional activation is not understood. Using reporter gene and DNA binding analyses, how PD genes are activated along the PD axis will be investigated. Second, a novel method to analyze the chromatin structure of PD gene regulatory sequences will be employed. Third, the role that cellular proliferation dynamics play in PD gene regulation will be investigated. These studies will impact public health in several ways. First, the mechanism by which secreted signals activate gene expression is common to many aspects of animal development and disease. Thus, a better understanding of these basic mechanisms is critical for deciphering how these pathways, when altered, contribute to diseases such as cancer. Second, many human birth defects are due to problems in the development of the appendages. As many of the transcription factors, signaling molecules, and underlying mechanisms controlling appendage development are conserved between Drosophila and humans, it is likely that a more comprehensive dissection of these processes in an experimentally powerful system such as Drosophila will provide important insights into these human birth defects.
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