In mammals, the biliary system, pancreas and liver all develop at 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. This represses positive basic helix-loop-helix genes such as Neurog3.
The expression of Hes1 is controlled by the Notch pathway.
|Defects in Notch signaling lead to accelerated pancreatic endocrine differentiation.|
Hes1 operates as a general negative regulator of endodermal endocrine differentiation. Defects in Notch signaling lead to accelerated pancreatic endocrine differentiation.
Mutations in JAG1 cause the Alagille syndrome in humans. This syndrome is characterized by poor development of the biliary system, and suggests that the Notch pathway is involved in normal biliary development.
In this study, researchers from Japan show that Hes1 is expressed in the extrahepatic biliary epithelium throughout development.
The team demonstrates that Hes1-deficient mice have gallbladder agenesis and severe hypoplasia of extrahepatic bile ducts.
Biliary epithelium in Hes1-/- mice ectopically expresses the proendocrine gene Neurog3. It differentiates into endocrine and exocrine cells, and forms acini and islet-like structures in the mutant bile ducts.
Dr Ryo Sumazaki's team concluded, "Biliary epithelium has the potential for pancreatic differentiation".
"Hes1 determines biliary organogenesis by preventing the pancreatic differentiation program, probably by directly repressing transcription of Neurog3".