Revised Abtract: The TGFbeta signal transduction pathways regulate cell growth and differentiation, cell migrations, and cell death. Some of the pathways are involved in establishing the basic body plan during embryogenesis in nematodes, flies, and vertebrates, while others regulate the development of specific tissues such as kidneys or bones. They also regulate wound healing and some immunological processes. Not surprisingly, TGFbeta components are implicated in a wide variety of human diseases and cancer-multiple components of the pathway are confirmed tumor suppressors. For these reasons, TGFbeta is one of the most important signaling pathways. Elucidating how its signals are mediated is of considerable interest. The overall goals of this project are to identify components of the signaling pathway in C. elegans, to determine how these proteins function during development, and to examine in detail one of the outputs of the pathway--the regulation of body/cell size. During the first funding period of this grant , we characterized three genes in C. elegans, sma-2, sma-3, and sma-4, that participate in TGFbeta signaling (the Sma/Mab pathway). These three genes, along with the Drosophila Mad gene, comprise the founders of the Smad family. Smads are the primary TGFbeta signal transducer, and have had a major impact on our understanding of how signals are sent. In addition, we cloned the first mouse Smads and showed they function downstream of the receptors. Based upon the mutant phenotypes exhibited from the C. elegans Smad genes, we performed genetic screens to find new components of the Sma/Mab pathway in C. elegans, which has resulted in the identification of the ligand, the type I receptor, schnurri, and several other new loci. We now propose 1) to characterize and clone other loci from our genetic screens, 2) to use RNAi and """"""""reverse genetic"""""""" techniques to make mutants in C. elegans homologs that have been proposed to function in TGFbeta signaling, but for which there is little supporting molecular genetic data, 3) to use cellular and biochemical methods to further characterize the Smads and other genes cloned from our screen, and 4) to determine how TGFbeta regulates body/cell size in C. elegans. Understanding how TGFbeta signals will provide insights into its important developmental roles how to eventually manipulate the pathway to control cellular proliferation of cancerous cells.
| Savage-Dunn, C; Tokarz, R; Wang, H et al. (2000) SMA-3 smad has specific and critical functions in DBL-1/SMA-6 TGFbeta-related signaling. Dev Biol 223:70-6 |
