Sox17 and the hepato-pancreato-biliary system

As the name indicates, the HPB consists of the liver, pancreas, gallbladder as well as the ductal and vascular network that link these vital organs. Diseases of these organs are a major cause of morbidity and mortality that include congenital abnormalities, toxicities, ductal obstructions, viral infections, cancer and diabetes. Sox17 is one of 20 different Sox genes expressed in mammals and, like other members of the gene family, has indispensable functions in regulating lineage specification and developmental potency. During gastrulation, mice lacking Sox17 function fail to undergo primary body-axis rotation and exhibit severe posterior defects. Sox17-null embryos also fail to express Pdx1, a key factor for pancreatic outgrowth and development. Dysregulation of Sox17 in endodermal cells causes biliary atresia, acute hepatitis, gallbladder agenesis, and ectopic pancreatic development. We have identified both proximal and distal cis-regulatory elements that are important for Sox17 expression. Mice with discrete mutations of these elements exhibit a wide range of abnormalities in the HPB system that range from mild to severe. We are studying how these mutations affect formation and function of the HPB system.