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:
- What is the precise role of Sox17 in endoderm development?
- What is the genetic program controlled by Sox17?
- What is the relationship between Sox17 and the other transcription factors and growth factors that specify the endodermal precursors?
- How does Sox17 biochemically interact with growth factor signaling pathways to regulate the expression of its target genes?
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.