Bile Duct Development and the Notch Signaling Pathway

Intrahepatic bile duct development is a sophisticated process that begins with a simple, perivenular arrangement of hepatoblasts and ends with an intricate, arborizing, hierarchical network of ducts that navigate the liver parenchyma, contributing to liver health and disease not only via drainage of bile but via direct and indirect interactions with surrounding cells. Development of the intrahepatic bile ducts depends upon cell specification and subsequent morphogenesis, both involving intercellular signaling through the Notch pathway. Alteration of this pathway by mutations in critical Notch ligands and/or Notch receptors disrupts normal intrahepatic bile duct formation and leads to the hepatobiliary phenotype seen in Alagille syndrome. More complete insight into the complexities of intrahepatic bile duct development and the signaling pathways involved (Notch and others) is a requisite preamble to defining cellular and molecular therapies with the potential of attenuating, or reversing, biliary injury in Alagille syndrome and other cholangiopathies.