Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha.
Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha.
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DOI：
10.1101/gad.14.4.464
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发表时间：
2000-02
影响因子：
10.5
通讯作者：
Jixuan Li;Gang Ning;Stephen A. Duncan
中科院分区：
文献类型：
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作者：
Jixuan Li;Gang Ning;Stephen A. Duncan
HNF-4 α是核激素受体家族的转录因子，在肝脏发育开始时在肝憩室中表达。缺乏HNF-4 α的小鼠胚胎由于内脏内胚层功能障碍而不能完成原肠胚形成。迄今为止，这种早期胚胎致死性阻止了对HNF-4 α对肝脏发育和肝细胞分化的贡献的任何分析。然而，我们已经表明，HNF-4 α（-/-）胚胎与四倍体胚胎衍生的野生型内脏内胚层互补挽救了这种早期发育停滞，并允许HNF-4 α（-/-）胚胎正常进行到妊娠中期发育阶段。对这些拯救的胚胎的检查显示，HNF-4 α是肝的特化和早期发育的标志。然而，HNF-4 α（-/-）胎肝未能表达大量基因，这些基因在分化的肝细胞中的表达对功能性肝实质至关重要，包括编码几种载脂蛋白、代谢蛋白和血清因子的基因。此外，我们已经证明，HNF-4 α是必不可少的表达转录因子HNF-1 α和PXR在胎儿肝脏。因此，我们得出结论，HNF-4 α在哺乳动物肝脏发育过程中对肝细胞分化至关重要，对代谢调节和肝脏功能也至关重要。
HNF-4alpha is a transcription factor of the nuclear hormone receptor family that is expressed in the hepatic diverticulum at the onset of liver development. Mouse embryos lacking HNF-4alpha fail to complete gastrulation due to dysfunction of the visceral endoderm. This early embryonic lethality has so far prevented any analyses of the contribution of HNF-4alpha toward liver development and hepatocyte differentiation. However, we have shown that complementation of HNF-4alpha(-/-) embryos with a tetraploid embryo-derived wild-type visceral endoderm rescues this early developmental arrest and allows HNF-4alpha(-/-) embryos to proceed normally through midgestation stages of development. Examination of these rescued embryos revealed that HNF-4alpha was dispensable for specification and early development of the liver. However, HNF-4alpha(-/-) fetal livers failed to express a large array of genes whose expression in differentiated hepatocytes is essential for a functional hepatic parenchyma, including genes encoding several apolipoproteins, metabolic proteins, and serum factors. In addition, we have demonstrated that HNF-4alpha is essential for expression of the transcription factors HNF-1alpha and PXR within the fetal liver. We therefore conclude that HNF-4alpha is both essential for hepatocyte differentiation during mammalian liver development and also crucial for metabolic regulation and liver function.