Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome

TLDR

Mutations in the Notch ligand JAG1 cause Alagille syndrome, a multisystem disorder marked by a severe reduction of intrahepatic bile ducts and variable cardiac, ocular, skeletal, craniofacial, and renal abnormalities, yet the molecular basis for this spectrum remains unclear. The study investigates whether Jag1 loss specifically in portal vein mesenchyme cells induces the hepatic manifestations of Alagille syndrome. The authors inactivated Jag1 in SM22α‑positive portal vein mesenchyme cells of mice to assess its impact on bile duct formation. Jag1 loss in SM22α‑positive portal vein mesenchyme cells caused defective bile duct development beyond the ductal plate, with cytokeratin‑19–positive cells unable to form biliary tubes, revealing distinct Jag1‑dependent and –independent stages of intrahepatic bile duct formation.

Abstract

Mutations in the human Notch ligand jagged 1 (JAG1) result in a multi-system disorder called Alagille syndrome (AGS). AGS is chiefly characterized by a paucity of intrahepatic bile ducts (IHBD), but also includes cardiac, ocular, skeletal, craniofacial and renal defects. The disease penetration and severity of the affected organs can vary significantly and the molecular basis for this broad spectrum of pathology is unclear. Here, we report that Jag1 inactivation in the portal vein mesenchyme (PVM), but not in the endothelium of mice, leads to the hepatic defects associated with AGS. Loss of Jag1 expression in SM22α-positive cells of the PVM leads to defective bile duct development beyond the initial formation of the ductal plate. Cytokeratin 19-positive cells are detected surrounding the portal vein, yet they are unable to form biliary tubes, revealing an instructive role of the vasculature in liver development. These findings uncover the cellular basis for the defining feature of AGS, identify mesenchymal Jag1-dependent and -independent stages of duct development, and provide mechanistic information for the role of Jag1 in IHBD formation.