Transforming growth factor beta (TGFbeta) related ligands regulate many aspects of cell differentiation and function, and components of the signaling pathway act as tumor suppressors involved in human cancers. In the nematode C. elegans, a TGFbeta-related signaling pathway, the dbl-1 pathway, controls body size and male tail morphogenesis. Studies of this pathway have previously been fruitful in identifying conserved signaling components, including the Smad signal transducers SMA-2, SMA-3, and SMA-4. Smad proteins are cytoplasmic components that are directly regulated by activated TGFbeta receptors to translocate into the nucleus and generate transcriptional responses. Given the diversity and cell type specificity of TGFbeta responses, this simple Smad signaling mechanism must require modulation by other signaling components. To identify additional components of the dbl-1 pathway and in particular those that confer specific pathway responses, a forward genetic screen for additional mutations affecting body size was performed. This screen identified several new genes, including sma-20. Preliminary analysis of sma-20 mutant phenotypes suggests that it plays spatially and temporally specific roles in dbl-1 signaling. To characterize the roles of sma-20 in body size regulation, male tail development, and TGFbeta-related signal transduction, we propose to use genetic, molecular, and phenotypic analyses of sma-20. Our goals are to (1) determine the complete loss of function (null) phenotype of sma-20; (2) map and positionally clone sma-20; and (3) analyze sma-20 cellular and temporal focus of action. These experiments will provide educational and scientific training opportunities for a graduate student and one or more undergraduate students at Queens College, CUNY. Since TGFbeta superfamily ligands and their receptors, the Smads, and Schnurri are conserved through distant animal phyla, studying new components in a genetically tractable model organism should provide insight into their functions in other organisms as well.
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