Shortly after endoderm tissue is formed in the early embryo, it becomes patterned, so that some of it gives rise to the foregut while other regions give rise to the hindgut. The foregut endoderm contains the progenitor cells that will give rise to the liver, pancreas, thyroid and lungs, whereas the hindgut domain gives rise to the intestine.

This patterning process, which progressively subdivides the endoderm into organ domains, begins during gastrulation and continues throughout early development, ensuring that the organs form in the correct position in the body. The molecular mechanisms that control this are poorly understood, but appear to be mediated by a series of growth factor interactions between the endoderm and surrounding mesoderm. One of the first manifestations of this patterning is the asymmetric expression of genes such the homeobox transcription factor Hhex in the foregut progenitor cells. Hhex is a homeodomain transcription factor that is essential for anterior endoderm and liver development.

We are trying to understand the molecular mechanisms that pattern the embryonic endoderm into organ domains. Our recent studies have found that different levels of Wnt, BMP and FGF growth factors in different parts of the embryo are a key step in patterning the endoderm into foregut and hindgut domains. Moreover these growth factors are used over and over again with different roles at different times and places in the embryo. We have shown that, shortly after gastrulation Wnt signaling must be repressed in the anterior endoderm by the secreted protein Sfrp5 in order to promote the development of foregut progenitor cells and the liver, lungs and pancreas. In contrast, high levels of Wnt in the posterior promote hindgut progenitors and intestinal differentiation. Using mouse genetics and transgenic frog embryos, which express green fluorescent protein under the control of the hhex promoter, we are characterizing how Wnts, BMP and Nodal growth factors control the complex transcriptional program of foregut development.

These studies will provide essential information on the genetic pathways controlling the earliest steps in digestive system development. In recent collaborations with the Wells and Shroyer labs these developmental paradigms have been utilized to direct the differentiation of human stem cells into intestinal tissue.