The broad goal of my research program is to understand how factors in the TGFbeta family regulate embryonic development in the amphibian Xenopus laevis. Studies using Xenopus and other amphibians have made seminal contributions to the understanding of vertebrate development and mechanisms that regulate cell differentiation. In vertebrate embryos activin, Vg1, nodal and BMP factors are involved in the induction and patterning of mesodermal tissues. In Xenopus, activin, Vg1 and nodal proteins induce dorsal mesoderm, such as head tissues, notochord (the embryonic backbone) and muscle, while BMPs induce bentral mesoderm such as blood. Past efforts of the principal investigator have contributed to the understanding of the function of activin, Vg1 and BMPs in Xenopus development. The proposed research will use Xenopus to investigate the embryonic function of signal transduction molecules in the MAD protein family, which convey signals from TGFbeta growth factor receptors. Several MAD-related genes have been identified in vertebraes, and of these, MAD1 and MAD2 have been shown to function in the development of Xenopus embryos. MAD1 transduces signals from BMP receptors and MAD2 transduces signals from activin receptors, or receptors for factors with activin-like effects, such as Vg1 and nodal. MAD proteins also represent a new class of tumor suppressor genes: mutations in MAD2 DPC4 contribute to colon and pancreatic tumors, respectively. MADs are potential targets for therapeutic intervention in cancer. Our proposed examination on MAD proteins will thus provide fundamental information about the mechanisms of TGFbeta signal transduction, vertebrate embryogenesis, and carcinogenesis. Experiments will investigate several topics: (a) The spatial and temporal expression of MAD1 and MAD2 proteins will be examined over the course of embryogenesis, and their behavior (e.g. chemical modification, subcellular distribution) in response to TGFbeta growth factors will be monitored. (B) MAD1 and MAD2 will be mutagenized and assayed in embryos to define protein domains and key amino acids that are responsible for their particular biological activitites and biochemical responses to receptors in the TGFbeta family. (C) A genetic screen in yeast wil be performed to isolate proteins that interact with MAD1 and MAD2 and potentially function as other components in TGFbeta signal transduction pathways.
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