Zebrafish hhex-null mutant develops an intrahepatic intestinal tube due to de-repression of cdx1b and pdx1
Zebrafish hhex-null mutant develops an intrahepatic intestinal tube due to de-repression of cdx1b and pdx1
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斑马鱼 hhex 无效突变体由于 cdx1b 和 pdx1 的去抑制而发育出肝内肠管
DOI：
10.1093/jmcb/mjy068
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发表时间：
2019-06-01
影响因子：
5.5
通讯作者：
Peng, Jinrong
中科院分区：
文献类型：
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作者：
Gao, Ce;Huang, Weidong;Peng, Jinrong
肝胰管（HPD）系统连接肝脏和胰腺与肠管，由肝外胆管、胆囊和胰管组成。造血表达的同源异型盒（Hhex）蛋白在HPD的形成中起重要作用，但其分子机制仍不清楚。在这里，我们表明，斑马鱼hhex无效突变体未能开发的HPD系统，其特征在于缺乏胆汁标记膜联蛋白A4和HPD标记sox9b。突变HPD系统的肝胆管部分被肝内肠管取代，其特征在于表达肠标志物脂肪酸结合蛋白2a（fabp2a）。细胞谱系分析表明，该肝内肠管并非起源于肝细胞或胆管细胞。进一步分析表明cdx1b和pdx1在肝内肠管异位表达，敲低cdx1b和pdx1可恢复突变体中sox9b的表达。染色质免疫沉淀分析表明Hhex与pdx1和cdx1b基因的启动子结合抑制其表达。因此，我们建议，Hhex，Cdx1b，Pdx 1，和Sox 9b形成一个遗传网络管理模式和形态学的HPD和消化道系统在斑马鱼。
The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder, and pancreatic duct. Haematopoietically expressed-homeobox (Hhex) protein plays an essential role in the establishment of HPD; however, the molecular mechanism remains elusive. Here, we show that zebrafish hhex-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The hepatobiliary duct part of the mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty acid-binding protein 2a (fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 are expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 could restore the expression of sox9b in the mutant. Chromatin-immunoprecipitation analysis showed that Hhex binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that Hhex, Cdx1b, Pdx1, and Sox9b form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish.