Wharton 96-04769 The long term goal of the research outlined in this proposal is to understand how TGF-Beta signaling molecules facilitate the communication between cells. Cellular communication is essential to the proper manifestation of cell movements, growth and differentiation in multi-cellular organisms. Members of the transforming growth factor-Beta (TGF-Beta) superfamily of cell signaling molecules are found in both invertebrates and vertebrates, from C.elegans to humans. The diverse roles performed by these signaling factors during development has been attributed to the dimeric nature of these ligands and the multiple combinations of monomer/monomer as well as ligand/receptor associations possible. During development cells must receive and interpret many different signals and it is essential to our understanding of development that we elucidate the process by which this occurs. The developmental consequences and in vivo regulation of TGF-Beta signaling are best understood for the Drosophila member, dpp. As a first step towards determining the functions of two different TGF-Beta signals and investigating the means by which their signals are interpreted, Dr. Wharton previously isolated a second member in Drosophila, the 60A gene, made mutations in the gene and determined that it is essential for embryogenesis and adult limb development. In this proposal, she intends to define the specifics of these requirements by 1) identifying the tissues in which 60A is required through the generation of mosaic clones and analysis of mutant phenotypes. She will 2) determine the developmental consequences of 60A function by examining the effect of 60A mutations on genes known to be important in patterning the midgut and the adult eye and wing. She will also examine the regulation of 60A by these genes. She will address the potential for overlap of 60A and dpp signaling using misexpression, generation of mutant clones and analysis of downstream factors. She intends to investigate the me chanism by which 60A signals and compare it to what is known for dpp signaling through 3) the identification of components mediating 60A signaling. Potential genetic interactions with mutations in known TGF-Beta signaling components will be investigated. Her findings will provide insight into the dynamics of cell signaling in the context of a developing organism. Understanding the in vivo function of TGF-Beta signaling factors and the mechanisms by which they signal will ultimately aid in our knowledge of fundamental processes in vertebrates, as well as in invertebrates. Understanding the biology of cell signaling is central to many medical applications and will ultimately be useful in the prevention and treatment of disease.
