The long-term goal of this proposal is to elucidate the molecular basis of embryonic endoderm development in vertebrates. The endoderm layer of the embryo gives rise to the epithelial lining of the gastrointestinal tract, liver, lungs, pancreas, thyroid and thymus, but our understanding of endoderm formation lags behind that of mesoderm and neural development. The framework of a conserved molecular pathway that initiates endoderm development has recently been deduced. The endoderm specific transcription factor Sox17 is one of the most downstream components of this pathway and while the evidence suggests that it has a critical function, its precise role has not been determined. Furthermore, the molecular cascade downstream of Sox17 that directs endoderm differentiation is unknown. This proposal focuses on the role of Sox17 using Xenopus as a model system. In our published work and preliminary experiments we have discovered that Sox17 functionally interacts with the Wnt and TGF signaling pathways. We have identified direct target genes of Sox17 and our data suggests that beta-catenin and Smad2 are important transcription partners of Sox17. This proposal seeks to extend our understanding of Sox17 function and endoderm development with the following specific aims: 1. To better characterize the role of Sox17 in endoderm formation. 2. To determine the function of several Sox17 target genes. 3. Examine how Sox17 interacts with the Wnt and TGF pathways to regulate endodermal genes. 4. Determine the molecular basis of Sox17's interaction with beta-catenin and Smad2. This research will further our understanding of endoderm development and how Sox, Wnt and TGF pathways are regulated. This information will be useful for directing the differentiation of stem cells along endodermal lineages. It may also provide insight into congenital diseases or cancers associated with defects in endoderm development, as well as mutation in Sox proteins, Wnt and TGF signaling components.
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