Transcriptional Control of Liver Development

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DESCRIPTION (provided by applicant): The liver develops from cells of the ventral foregut endoderm which differentiate into heptoblasts and proliferate into the adjacent mesenchyme to form the liver bud. Most of these cells mature into hepatocytes, but some of those surrounding the portal veins develop into the ductal plate, which gives rise to the bile ducts. In mice, this is followed by the formation of the hepatic arteries, thereby completing the portal triad. Defects in hepatogenesis are responsible for several pediatric liver diseases. This proposal aims to train the principal investigator (PI) for a research career focused on the study of liver development with the ultimate purpose of ameliorating these and other liver disorders. The goal of Specific Aims 1-3 is to characterize the regulatory networks controlling hepatogenesis. The Foxa family of winged helix transcription factors is expressed in the endoderm immediately before the onset of hepatogenesis, and they bind to the regulatory regions of a number of liver-specific genes. The first specific aim tests the hypothesis that Foxa1 and Foxa2 play a central role in the specification and further development of the liver. Mouse embryos lacking Foxa1 and Foxa2 throughout the endoderm will be generated; preliminary results indicate that in the absence of these factors, hepatic specification does not occur. The mechanism of Foxa function in liver development will be explored using protein and mRNA detection techniques to identify liver transcription factors whose expression is dependent on Foxa1 or Foxa2. In the second specific aim, these findings will be extended using chromatin immunoprecipitation combined with promoter microarray analysis to identify novel Foxa1 and Foxa2 target genes. The third specific aim will expand the focus to include the later stages of bile duct and hepatic artery development through the derivation of a transgenic mouse line allowing the analysis of ductal plate and biliary epithelial cell-specific gene expression. This data will be used to test the hypothesis that hepatic arteriogenesis requires inductive signals from developing bile ducts. Over the course of these studies, the PI will acquire laboratory skills, research training, and critical reagents which will enable him to begin work as an independent physician-scientist. The information which will be obtained from this and future investigations will improve our understanding of liver development and may enhance the diagnosis, treatment, and prevention of liver disease in humans.