O0041 HES1, A TRANSCRIPTIONAL REPRESSOR, CONTROLS BILIARY VERSUS PANCREATIC DEVELOPMENT

Abstract

Introduction: The biliary system, pancreas and liver all develop from the nearby fetal gut at almost the same time. However, the molecular mechanisms that determine the identity of each organ are unknown. Hes1 encodes the basic helix-loop-helix protein Hes1, which represses positive basic helix-loop-helix genes such as Neurogenin3. Expression of Hes1 is controlled by the evolutionarily conserved Notch pathway. Mutations in JAG1, encoding a Notch ligand, cause the Alagille syndrome, characterized by poor development of the biliary system, suggesting that the Notch pathway is involved in normal biliary development. In this study, we show that Hes1 acts like a molecular switch between biliary and pancreatic development. Methods: We examined the biliary system and other foregut-derived organs during embryogenesis in Hes1-deficient and wild-type mice. Results:Hes1 is expressed in the extrahepatic biliary epithelium throughout development and that Hes1-deficient mice show gallbladder agenesis and severe hypoplasia of extrahepatic bile ducts, although the intrahepatic bile ducts develop distinctly in the mutants. We did not find an increase in apoptotic cells in the mutant compared with wild-type biliary epithelium. The biliary epithelium in Hes1-deficient mice ectopically expresses the pro-endocrine gene Neurogenin3 and differentiates into endocrine cells, expressing glucagon (alpha cells), insulin (??eta cells), somatostatin (delta cells) and pancreatic peptide (PP-cells) and exocrine cells. The ectopic insulin-positive cells also co-expressed Ipf1, Isl1 and glut2, similarly to mature pancreatic ??eta cells. The mutant bile ducts also displays pancreatic morphology with the formation of acini and islet-like structure and thus the common bile duct of Hes1-deficient embryos was totally replaced by pancreatic tissue. Conclusion: Biliary epithelium has the potential for pancreatic differentiation and Hes1 determines extrahepatic biliary organogenesis by preventing the pancreatic differentiation program, most likely involving direcly repressing transcription of Neurogenin3.