Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome.
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.
Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Jennifer J
JJ
Hofmann
Ann C
AC
Zovein
Huilin
H
Koh
Freddy
F
Radtke
Gerry
G
Weinmaster
M Luisa
ML
Iruela-Arispe
D016738:Alagille Syndrome / Q000196:embryology* / Q000473:pathology*; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D001774:Blood Chemical Analysis; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002449:Cell Aggregation; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008099:Liver / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009024:Morphogenesis; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D010641:Phenotype; D011169:Portal Vein / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D055758:SOX9 Transcription Factor; D000072099:Serrate-Jagged Proteins; C527933:Sox9 protein, mouse