Endothelial and smooth muscle cell deletion of Jagged1 independently reconstitute the cardiac and hepatic defects of Alagille Syndrome

Mutations in the human Notch ligand Jagged1 (Jag1) result in a multisystem autosomal dominant disorder called Alagille Syndrome. The most frequent abnormalities associated with this syndrome include paucity of bile ducts in the liver, which often requires liver transplant, and a wide range of cardiac defects. Minor skeletal and ocular anomalies can also be present with varying degrees of penetration. To gain a more thorough understanding of the function of this ligand during development, we employed a strategy involving cell‐specific deletion of Jag1 in mice. We found that inactivation of Jag1 in smooth muscle cell progenitors leads selectively to the hepatic defects associated with Alagille Syndrome, without any observed cardiac defects. Jag1 expression in vascular smooth muscle precursors is required for the morphogenesis of the biliary ducts, revealing the instructive and essential role of the vasculature in liver morphogenesis. In contrast, the deletion of Jag1 in the endothelium led to a wide spectrum of cardiac anomalies but lacked any hepatic defects. Together, these findings uncover the cellular basis for the hepatic and cardiac abnormalities associated with Alagille Syndrome and provide mechanistic information as to the essential role of Jag1 in biliary duct morphogenesis and cardiac outflow tract development.