Our long term goals are to understand the role of TGFbeta signaling in development. In this proposal, we will investigate how the downstream specificity of TGFbeta signals is achieved. Specifically, our aims are: 1) To perform genetic suppressor screens of activated dpp type I receptors in Drosophila. Through comparison of suppressors obtained in two different tissues, or in one tissue with three different type I receptors, we will address the important issue of how the specificity of signaling is achieved. 2) To genetically characterize the new mutations obtained in the suppressor screens, in order to ascertain their roles in TGFbeta signaling. interesting ones will be cloned and molecularly characterized. 3). To study the cellular and biochemical aspects of TGFbeta signaling using cell culture. Drosophila cell cultures approaches will allow us to address questions regarding the structure-function of the Smads, as well as questions concerning the role of putative signal transducers isolated in our genetic screens. Thus, cell cultures studies will provide an important complement to our genetic studies. Genes will identify in our genetic screens will be further characterized in Drosophila cell lines along with know genes in the pathway, in order to gain a more complete picture of how their proteins function. 4) To determine how dpp signaling intersects with the cell death pathway. Recent studies have revealed many of the steps that lead to cell death, however, little is known about the growth factor signals that modulate the entry into apoptosis. We have discovered that excess signaling of the dpp pathway can cause apoptosis in the wing imaginal disk. We propose to study further the mechanisms by which dpp induces apoptosis. In addition, we will perform a genetic screen for suppressors of this phenotype to identify other genes which direct cell death in response to the dpp signal. These studies will allow us to identify tissue specific and receptor specific factors, providing insights into the downstream specificity of TGFbeta-like signaling.
