Conversion of biliary system to pancreatic tissue in Hes1-deficient mice
Conversion of biliary system to pancreatic tissue in Hes1-deficient mice
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DOI：
10.1038/ng1273
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发表时间：
2004-01-01
期刊：
影响因子：
30.8
通讯作者：
Matsui, A
中科院分区：
文献类型：
--
作者：
Sumazaki, R;Shiojiri, N;Matsui, A
哺乳动物的胆道系统、胰腺和肝脏几乎同时从附近的前肠发育而来。在这个复杂的区域，决定每个器官身份的分子机制是未知的。Hes1编码基本螺旋-环-螺旋蛋白Hes1（参考文献1），其抑制正向的基本螺旋-环-螺旋基因(2)，如Neurog3（参考文献3）。Hes1的表达受进化保守的Notch通路控制(4)。Hes1是内胚层内分泌分化的一般负调控因子（5,6），Notch信号缺陷导致胰腺内分泌分化加速（7,8）。编码Notch配体的JAG1的突变导致人类的Alagille综合征（9,10），其特征是胆道系统发育不良（11），这表明Notch通路也参与了正常的胆道发育。在整个发育过程中，Hes1在肝外胆道上皮中表达，Hes1缺陷小鼠2存在胆囊发育不全和肝外胆管严重发育不全。Hes1（-/-）小鼠胆道上皮异位表达内分泌前基因Neurog3（参考文献）。12,13)，分化为内分泌和外分泌细胞，并在突变的胆管中形成腺泡和胰岛样结构。因此，胆道上皮具有胰腺分化的潜力，Hes1通过阻止胰腺分化程序决定胆道器官发生，可能是通过直接抑制Neurog3的转录
The biliary system, pancreas and liver all develop from the nearby foregut at almost the same time in mammals. The molecular mechanisms that determine the identity of each organ in this complex area are unknown. Hes1 encodes the basic helix-loop-helix protein Hes1 (ref. 1), which represses positive basic helix-loop-helix genes(2) such as Neurog3 (ref. 3). Expression of Hes1 is controlled by the evolutionarily conserved Notch pathway(4). Hes1 operates as a general negative regulator of endodermal endocrine differentiation(5,6), and defects in Notch signaling lead to accelerated pancreatic endocrine differentiation(7,8). Mutations in JAG1, encoding a Notch ligand, cause the Alagille syndrome in humans(9,10), characterized by poor development of the biliary system(11), suggesting that the Notch pathway is also involved in normal biliary development. Here we show that Hes1 is expressed in the extrahepatic biliary epithelium throughout development and that Hes1-deficient mice 2 have gallbladder agenesis and severe hypoplasia of extrahepatic bile ducts. Biliary epithelium in Hes1(-/-) mice ectopically expresses the proendocrine gene Neurog3 (refs. 12,13), differentiates into endocrine and exocrine cells and forms acini and islet-like structures in the mutant bile ducts. Thus, biliary epithelium has the potential for pancreatic differentiation and Hes1 determines biliary organogenesis by preventing the pancreatic differentiation program, probably by directly repressing transcription of Neurog3