One of our long-term goals is to elucidate the molecular program controlling liver development. The liver provides many essential functions, and numerous liver pathologies are so life-threatening that transplantation is the only option.
Despite its physiological importance, the molecular basis of liver development is poorly understood. A better understanding will provide insight into congenital liver disease and facilitate efforts to produce therapeutically useful hepatic tissue from stem cells.
Over the last 10 years, studies have shown that FGF and BMP growth factors secreted from the heart mesoderm induce the liver from a subset of the foregut endoderm tissue. As a result the undifferentiated liver precursor cells known as “hepatoblasts” delaminate from the foregut epithelium and invade the adjacent mesenchyme to form the growing liver bud – a bulb of tissue emerging from the primitive gut tube. However, there are a number of important steps in this process that are not well understood and which our research is attempting to address using frog and mouse embryos as experimental models.
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- The earlier events that make the foregut progenitor cell competent to become liver in response to growth factors from the heart mesoderm are unclear. We are testing the hypothesis that this is controlled in part by the differential Wnt signaling events that pattern the endoderm. We are trying to understand the role of Wnt antagonists in this process and how early endoderm patterning is linked with subsequent organ induction.
- The genetic program that is initiated in the foregut progenitor cells by FGF and BMP signals from the mesoderm is unknown. Using the microsurgery of foregut tissue and global gene expression analysis, we have uncovered a number of novel target genes, and we are characterizing their function.
- There is evidence that FGF, BMP and Wnt growth factor signaling direct some foregut cells to become liver while nearby cells become pancreas or lung. Moreover, it is increasingly clear that growth factor signaling is very dynamic with the same growth factors having different roles at different times in development. We are investigating the mystery of how the FGF, BMP and Wnt signaling pathways interact and how these activities are regulated in time and space in the dynamically developing embryos.
The results of this proposal will provide novel information on the molecular mechanisms governing early hepatic development.