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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042572-04
Application #
6914835
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Klein, Steven
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$415,400
Indirect Cost
Name
Children's Hospital Med Ctr (Cincinnati)
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Kormish, Jay D; Sinner, Débora; Zorn, Aaron M (2010) Interactions between SOX factors and Wnt/beta-catenin signaling in development and disease. Dev Dyn 239:56-68
Li, Yan; Rankin, Scott A; Sinner, Debora et al. (2008) Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling. Genes Dev 22:3050-63
Woodland, Hugh R; Zorn, Aaron M (2008) The core endodermal gene network of vertebrates: combining developmental precision with evolutionary flexibility. Bioessays 30:757-65
Kirilenko, Pavel; Weierud, Frida K; Zorn, Aaron M et al. (2008) The efficiency of Xenopus primordial germ cell migration depends on the germplasm mRNA encoding the PDZ domain protein Grip2. Differentiation 76:392-403
McLin, Valerie A; Rankin, Scott A; Zorn, Aaron M (2007) Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development 134:2207-17
Zorn, Aaron M; Wells, James M (2007) Molecular basis of vertebrate endoderm development. Int Rev Cytol 259:49-111
Kirk, Edwin P; Sunde, Margaret; Costa, Mauro W et al. (2007) Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet 81:280-91
Sinner, Debora; Kordich, Jennifer J; Spence, Jason R et al. (2007) Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol 27:7802-15
Sinner, Debora; Kirilenko, Pavel; Rankin, Scott et al. (2006) Global analysis of the transcriptional network controlling Xenopus endoderm formation. Development 133:1955-66
Sartor, Maureen A; Zorn, Aaron M; Schwanekamp, Jennifer A et al. (2006) A new method to remove hybridization bias for interspecies comparison of global gene expression profiles uncovers an association between mRNA sequence divergence and differential gene expression in Xenopus. Nucleic Acids Res 34:185-200

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