The long-term goal of this project is to elucidate the molecular mechanisms controlling embryonic development of the digestive system. This will have a broad and significant impact on our understanding of human GI malformations, inform strategies to direct the differentiation of stem cells and provide new fundamental information on cell signaling in development and disease. Digestive system development is regulated by a series of growth factor signals between the endoderm and mesoderm, which are only partially understood. The fundamental mechanism of GI development are highly conserved between mammals and other vertebrate species and our previous studies using the experimental advantages of Xenopus embryos has helped inform strategies to induce human intestinal tissue from stem cells. Despite recent advances, fundamental gaps in our understanding of how foregut and hindgut progenitors are specified remain. In particular how the extracellular environment regulates combinatorial signaling dynamics at different stages of GI development, and how transcriptional specificity in response to these signal is achieved are largely unknown and the focus of this proposal. Our preliminary studies support the hypothesis that Secreted Frizzed Related Proteins (Sfrp) regulate the extracellular Fibronectin matrix to promote BMP signaling by a novel mechanism, and that Sfrps coordinate signaling crosstalk between BMP and Wnt growth factors to pattern the endoderm into foregut and hindgut progenitors.
Aim 1 will characterize the novel mechanisms by which Sfrps and Tolloid proteases modulate the Fibronectin matrix to regulate BMP signaling.
Aim 2 will determine the mechanisms that coordinate BMP and Wnt signaling.
Aim 3 will determine how differential activity of the BMP and Wnt signaling effectors Smad1 and beta-catenin are integrated on DNA cis-regulatory elements to control foregut versus hindgut transcription.

Public Health Relevance

The goal of this project is to elucidate the complex genetic pathways regulating embryonic development of the digestive system using an animal model. This is critical to understand congenital birth defects and digestive system diseases, which are a significant burden on human health. Our results will also continue to inform strategies to direct the differentiation of human stem cells into digestive organ tissue for disease modeling and ultimately cell replacement therapy.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK070858-06
Application #
8703974
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Nolan, Kristof; Kattamuri, Chandramohan; Luedeke, David M et al. (2013) Structure of protein related to Dan and Cerberus: insights into the mechanism of bone morphogenetic protein antagonism. Structure 21:1417-29
Zhang, Zheng; Rankin, Scott A; Zorn, Aaron M (2013) Different thresholds of Wnt-Frizzled 7 signaling coordinate proliferation, morphogenesis and fate of endoderm progenitor cells. Dev Biol 378:1-12
Rankin, Scott A; Kormish, Jay; Kofron, Matt et al. (2011) A gene regulatory network controlling hhex transcription in the anterior endoderm of the organizer. Dev Biol 351:297-310
Rankin, Scott A; Zorn, Aaron M; Buchholz, Daniel R (2011) New doxycycline-inducible transgenic lines in Xenopus. Dev Dyn 240:1467-74
Kormish, Jay D; Sinner, Debora; Zorn, Aaron M (2010) Interactions between SOX factors and Wnt/beta-catenin signaling in development and disease. Dev Dyn 239:56-68
Hellsten, Uffe; Harland, Richard M; Gilchrist, Michael J et al. (2010) The genome of the Western clawed frog Xenopus tropicalis. Science 328:633-6
Xu, Ke; Chong, Diana C; Rankin, Scott A et al. (2009) Rasip1 is required for endothelial cell motility, angiogenesis and vessel formation. Dev Biol 329:269-79
Rankin, Scott A; Hasebe, Takashi; Zorn, Aaron M et al. (2009) Improved cre reporter transgenic Xenopus. Dev Dyn 238:2401-8
Zorn, Aaron M; Wells, James M (2009) Vertebrate endoderm development and organ formation. Annu Rev Cell Dev Biol 25:221-51
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

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