Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome
Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome
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DOI：
10.1242/dev.052118
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发表时间：
2010-12-01
期刊：
影响因子：
4.6
通讯作者：
Iruela-Arispe, M. Luisa
中科院分区：
文献类型：
--
作者：
Hofmann, Jennifer J.;Zovein, Ann C.;Iruela-Arispe, M. Luisa
人类Notch配体锯齿蛋白1（JAG1）的突变会导致一种名为阿拉杰尔综合征（AGS）的多系统疾病。AGS的主要特征是肝内胆管（IHBD）缺乏，但也包括心脏、眼部、骨骼、颅面和肾脏缺陷。受影响器官的疾病外显率和严重程度可能有很大差异，这种广泛病理表现的分子基础尚不清楚。在此，我们报道在小鼠门静脉间充质（PVM）中而非内皮细胞中Jag1失活会导致与AGS相关的肝脏缺陷。PVM中平滑肌22α阳性细胞中Jag1表达缺失会导致胆管板初始形成之后的胆管发育缺陷。在门静脉周围可检测到细胞角蛋白19阳性细胞，但它们无法形成胆管，这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标志性特征的细胞基础，确定了胆管发育过程中间充质Jag1依赖和非依赖阶段，并为Jag1在肝内胆管形成中的作用提供了机制信息。
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 SM22 alpha-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.