Lee Catherine S, Friedman Joshua R, Fulmer James T, Kaestner Klaus H
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Nature. 2005 Jun 16;435(7044):944-7. doi: 10.1038/nature03649.
The specification of the vertebrate liver is thought to occur in a two-step process, beginning with the establishment of competence within the foregut endoderm for responding to organ-specific signals, followed by the induction of liver-specific genes. On the basis of expression and in vitro studies, it has been proposed that the Foxa transcription factors establish competence by opening compacted chromatin structures within liver-specific target genes. Here we show that Foxa1 and Foxa2 (forkhead box proteins A1 and A2) are required in concert for hepatic specification in mouse. In embryos deficient for both genes in the foregut endoderm, no liver bud is evident and expression of the hepatoblast marker alpha-fetoprotein (Afp) is lost. Furthermore, Foxa1/Foxa2-deficient endoderm cultured in the presence of exogenous fibroblast growth factor 2 (FGF2) fails to initiate expression of the liver markers albumin and transthyretin. Thus, Foxa1 and Foxa2 are required for the establishment of competence within the foregut endoderm and the onset of hepatogenesis.
脊椎动物肝脏的特化被认为是一个两步过程，首先在前肠内胚层建立对器官特异性信号作出反应的能力，随后诱导肝脏特异性基因。基于表达和体外研究，有人提出Foxa转录因子通过打开肝脏特异性靶基因内紧密的染色质结构来建立能力。在此，我们表明Foxa1和Foxa2（叉头框蛋白A1和A2）在小鼠肝脏特化过程中共同发挥作用。在前肠内胚层中两个基因均缺失的胚胎中，没有明显的肝芽，并且肝母细胞标志物甲胎蛋白（Afp）的表达消失。此外，在前肠内胚层中培养的缺乏Foxa1/Foxa2的细胞，在外源成纤维细胞生长因子2（FGF2）存在的情况下，无法启动肝脏标志物白蛋白和甲状腺素运载蛋白的表达。因此，Foxa1和Foxa2对于前肠内胚层能力的建立和肝发生的起始是必需的。
