Alagille Syndrome (AGS) and Notch Signaling

Alagille syndrome (AGS) is a rare autosomal dominant multisystemic dysmorphogenetic disorder caused by a defective Notch signaling due to mutations in a Notch ligand (JAG1) or, less frequently, in a Notch receptor (NOTCH2). AGS is associated with an incomplete development of the intrahepatic bile ducts; in fact, liver disease is characterized by bile duct paucity, with variable degrees of cholestasis, progressive jaundice, itching, and failure to thrive. Treatment is symptomatic, and liver transplantation is sometimes necessary.

The Notch pathway is an evolutionarily conserved signaling system that regulates cell fate decisions in stem cells and plays a major role in the development of the biliary tree. Studies in AGS lead to improved understanding of the role of Notch signaling not only in biliary ontogenesis, but also after birth, in biliary repair and carcinogenesis. By regulating the homotypic and heterotypic cross-talk between several types of liver cells. Deriving from observations on patients with AGS undergoing liver transplantation, we have studied Notch signaling in the context of the general mechanisms of epithelial repair and regeneration. Using pharmacologic and genetic approaches, we discovered that Notch signaling is reactivated in adult life during chronic liver diseases with a role on the activation of hepatic progenitor cells (HPCs) and ductal morphogenesis. These studies were adding important pieces to the

puzzle of the mechanisms of liver repair, a fundamental step for preserving organ function and prolonging survival of patients with liver disease

Notch signaling is also involved in the biliary phenotypic switch of transdifferentiating hepatocytes and possibly, in intrahepatic cholangiocarcinoma (CCA).