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The endoderm gives rise to the epithelial lining of the respiratory and gastrointestinal tract as well as to the liver, lungs, pancreas, thyroid and thymus. Recent studies have begun to elucidate an evolutionarily conserved molecular pathway that specifies the endoderm during gastrulation and this information has helped in our ability to differentiate human endoderm tissue from stem cells.
This molecular pathway includes activity of a number of transcription factors and growth factors of the Nodal family. The HMG box transcription factor Sox17 is a key component of this pathway and is essential for endoderm formation; however, the molecular events controlled by Sox17 are largely unknown.
We are trying to address the following questions:
Using high throughput analyses such as microarray and NextGen sequencing, we are investigating the global genetic program of endoderm formation during Xenopus gastrulation. Our studies have identified Sox17 target genes and have shown that Sox17 physically interacts with beta-catenin, a key component of the Wnt signaling pathway, and this enhances the ability of Sox17 to activate transcription of its target genes. Work by our group and others have shown that most of the gene pathways controlling endoderm formation is conserved between frogs, fish, mice and humans.
We have also found that many Sox factors interact with beta-catenin / Tcf and modulate cellular responses to Wnt growth factor signaling − a finding that may have broad implications for diseases such as cancer.
Ongoing studies are focused on elucidating the role of novel Sox17-target genes and examining the complex gene regulatory network controlled by Sox17 and Nodal signaling.
Sinner D, Kordich JJ, Opoka R, Rankin SA, Lin SC, Jonatan D, Zorn AM, Wells JM. Sox17 and Sox4 differentially regulate beta-catenin/TCF activity and proliferation of carcinoma cells. Mol Cell Biol. 27:7802-7815. 2007.
Zorn AM, Wells JM. Molecular basis of vertebrate endoderm development. International Review of Cytology. 259:49-111. 2007.
Sinner D, Kirilenko P, Rankin S, Wei E, Howard L, Kofron M, Heasman J, Woodland HR, Zorn AM. Global analysis of the transcriptional network controlling Xenopus endoderm formation. Development. 133:19555-1966. 2006.
Sinner D, Rankin S, Lee M, Zorn AM. Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development. 131:3069-3080. 2004.
Gilchrist M, Zorn AM, Voigt J, Smith JC, Papalopulu N, Amaya E. Defining a large set of full-length clones from a Xenopus tropicalis EST project. Dev Bio. 271:498-516. 2004.
D'Souza A, Lee M, Taverner N, Mason J, Carruthers S, Smith JC, Amaya E, Papalopulu N, Zorn AM. Molecular components of the endoderm specification pathway in Xenopus tropicalis. Dev Dyn. 226:118-127. 2003.
Zorn AM, Barish G, Williams B, Lavander P, Klymkowsky M, Varmus HE. Regulation of Wnt signalling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin. Molecular Cell. 4:487-498. 1999.
click to enlarge
A section of an early blastula (left) shows a group of several hundred presumptive endodermal cells (orange) that ultimately give rise to the entire GI tract and associated organs (middle). A vast array of highly specialized epithelial cell types are present in the GI tract, as illustrated by a histological section of the gall bladder (right).
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