TGF Beta pathways play important roles in human development and disease; mutations in TGF Beta pathways cause uncontrolled cell growth and metastasis in cancers, and diseases such as hereditary hemorrhagic telangiectasis type 2. A TGF Beta pathway in C. elegans functions in a neuroendocrine event that controls the development of a specialized larval form called dauer, in addition to controlling other behaviors and phenotypes. These genes are: daf7 (a TGF Beta ligand), daf1 and daf4 (receptor kinases), and daf8 and daf14 (Smad transcription factors). The daf3 gene, also a Smad, mutates to a dauer defective phenotype, and genetic analysis suggests that this gene is negatively regulated by the other five genes.
Their aims are: 1) To study the function of the gene daf5. The dauer defective phenotype and epistasis relationships of daf5 suggests that it, like daf3, may be negatively regulated by the TGF Beta pathway. They will determine the expression pattern of daf5 to identify cells in which it functions, and they will test whether the expression or subcellular localization of daf5 is regulated by other genes that control dauer. 2) To characterize new suppressors of the dauer constitutive phenotype of daf7. They have 85 suppressors in hand; analysis of a subset of these suppressors has revealed four new loci that control dauer formation. They will determine which of the other suppressors are also alleles of new genes, and test all of the new loci for function in the events controlled by the TGF Beta pathway. They will determine if the new loci control the expression or subcellular localization of daf3 and daf5. These analyses will suggest models for the molecular mechanism by which these new genes function. They will then select two loci for cloning, which will allow them to study the function of these genes in dauer formation and the TGF Beta pathway. 3) To identify cells in which the daf1 receptor kinase is expressed, and test these cells for function by laser ablation. They will also use tissue specific and cell type specific promoters to express daf4, daf8, daf14 and daf3 to test hypotheses for where these genes function. They will study the biochemical relationships of the receptors and Smads in a tissue culture system to test hypotheses for regulatory relationships. The achievement of these aims will allow them to elucidate the function of a TGF Beta pathway in controlling neuroendocrine mediated events in C. elegans development, and will result in the identification new genes that participate in this pathway. The involvement of TGFBeta and neuroendocrine signaling in important developmental processes and diseases suggests important implications for human health.
| da Graca, Li S; Zimmerman, Karen K; Mitchell, Melissa C et al. (2004) DAF-5 is a Ski oncoprotein homolog that functions in a neuronal TGF beta pathway to regulate C. elegans dauer development. Development 131:435-46 |
