The role of Notch receptor expression in bile duct development and disease
The role of Notch receptor expression in bile duct development and disease
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DOI：
10.1002/path.1615
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发表时间：
2004-09-01
影响因子：
7.3
通讯作者：
Crosby, HA
中科院分区：
文献类型：
--
作者：
Flynn, DM;Nijjar, S;Crosby, HA
Jagged 1基因（Notch信号通路的配体）的突变与Alagille综合征（AGS）的发病机制有关，导致胆管缺乏。最近，AGS的小鼠模型表明Notch 2受体以及Jagged 1可能存在异常。Notch受体的表达模式尚未在发育中的人类肝脏或儿科肝脏中描述。通过RT-PCR和免疫组化检测Notch受体和配体在胎儿、儿童正常和患病人肝脏中的表达。RT-PCR显示Notch 1 -4 mRNA表达。在胎肝中，Notch 3蛋白表达于间充质细胞，与表达Jagged 1的导管板细胞紧密相邻。在小儿正常肝脏中，Notch 1和Notch 2存在于成熟胆管细胞上。Notch表达在疾病中改变，AGS与肝外胆道闭锁（EHBA）和α 1-抗胰蛋白酶缺乏症（α 1AT）有明显差异。在存在广泛的小管反应的AGS中，Jagged 1在小管反应细胞（DRC）上表达，沿着有显著的Notch 2和Notch 3染色。当胆管缺乏时，Notch 2和Notch 3在剩余的胆管上皮细胞上不表达。在EHBA和alpha 1AT中，在DRC上未观察到Notch受体表达。相反，Notch 2和Notch 3由基质细胞表达。在所有疾病中，Notch 3表达于汇管区和纤维间隔的新生血管上。总之，Notch 3在胆管板形成时与Jagged 1非常接近地表达，表明Notch 3对胆管发育很重要。Notch 2和Notch 3在DRCs上的AGS中的表达证实了这些受体在这种疾病的发病机制中可能是重要的。需要进一步的研究来调查Notch 2和Notch 3在肝脏发育的其他时期的存在，并阐明Notch信号在儿科胆汁淤积中的作用。版权所有（C）2004大不列颠和爱尔兰病理学会。出版社：John Wiley Sons，Ltd
Mutations in the Jagged1 gene, a ligand for the Notch signalling pathway, have been implicated in the pathogenesis of Alagille syndrome (AGS), resulting in bile duct paucity. Recently, a mouse model for AGS suggested that abnormalities of the Notch2 receptor, as well as of Jagged1, may be present. Expression patterns of Notch receptors have not been described in the developing human liver or in paediatric liver. The expression of Notch receptors and ligands was examined in fetal, paediatric normal, and diseased human liver by RT-PCR and immunohistochemistry. RT-PCR showed Notch1-4 mRNA expression to be present. In fetal liver, Notch3 protein was expressed on mesenchymal cells, closely adjacent to ductal plate cells that expressed Jagged1. In paediatric normal liver, Notch1 and Notch2 were present on mature bile duct cells. Notch expression was altered in disease, with distinct differences in AGS from extrahepatic biliary atresia (EHBA) and alpha1-anti-trypsin deficiency (alpha1AT). In AGS, where extensive ductular reaction was present, Jagged1 was expressed on ductular reactive cells (DRCs), along with marked Notch2 and Notch3 staining. Where there was ductular paucity, Notch2 and Notch3 were not expressed on remaining biliary epithelial cells. In EHBA and alpha1AT, Notch receptor expression was not seen on DRCs. Instead, Notch2 and Notch3 were expressed by stromal cells. In all diseases, Notch3 was expressed on neovessels in portal tracts and cirrhotic fibrous septa. In conclusion, Notch3 is expressed in close proximity to Jagged1 at the time of ductal plate formation, suggesting that Notch3 is important for bile duct development. The expression of both Notch2 and Notch3 in AGS on DRCs confirms that these receptors may be important in the pathogenesis of this disease. Further studies are required to investigate the presence of Notch2 and Notch3 at other periods in liver development and to clarify the role of Notch signalling in paediatric cholestases. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.