Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Development. 2010 Dec;137(23):4061-72. doi: 10.1242/dev.052118.
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.
人类 Notch 配体 jagged 1（JAG1）的突变导致一种称为 Alagille 综合征（AGS）的多系统疾病。AGS 的主要特征是肝内胆管（IHBD）稀少，但也包括心脏、眼部、骨骼、颅面和肾脏缺陷。受影响器官的疾病渗透和严重程度可能有很大差异，这种广泛病理学的分子基础尚不清楚。在这里，我们报告说 Jag1 在门静脉间质（PVM）中的失活，但不在内皮细胞中，导致与 AGS 相关的肝缺陷。PVM 中 SM22α 阳性细胞中 Jag1 表达的丧失导致胆管发育缺陷，超出了胆管板的初始形成。在门静脉周围检测到细胞角蛋白 19 阳性细胞，但它们不能形成胆管，揭示了脉管系统在肝脏发育中的指导作用。这些发现揭示了 AGS 定义特征的细胞基础，确定了间质 Jag1 依赖和独立的胆管发育阶段，并为 Jag1 在 IHBD 形成中的作用提供了机制信息。
