Hepatocyte nuclear factor 4α is essential for embryonic development of the mouse colon
Hepatocyte nuclear factor 4α is essential for embryonic development of the mouse colon
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DOI：
10.1053/j.gastro.2006.01.003
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发表时间：
2006-04-01
期刊：
影响因子：
29.4
通讯作者：
Duncan, SA
中科院分区：
文献类型：
--
作者：
Garrison, WD;Battle, MA;Duncan, SA
背景与目的：肝细胞核因子4α(HNF4α)是一种转录因子，在肝细胞分化和肝脏发育中起重要作用。它还参与调节作用于下胃肠道上皮细胞的基因表达。这意味着HNF4α可能是肠道发育所必需的。方法：用Cre-loxP技术在胎结肠上皮细胞中去除HNF4a，建立小鼠胚胎。通过组织学、免疫组织化学、DNA微阵列、逆转录聚合酶链式反应、凝胶迁移率改变分析和染色质免疫沉淀分析相结合的方法检测胚胎，以确定HNF4α缺失对结肠发育的影响。结果：胚胎发育至E18.5时，其结肠内HNF4α缺失。虽然出现了结肠发育的早期阶段，但HNF4α零结肠未能形成正常的隐窝。此外，杯状细胞的成熟受到干扰，一系列编码在结肠功能中具有不同作用的蛋白质的基因表达受到干扰。在结肠中表达依赖于HNF4α的几个基因在推测的转录调节区中含有HNF4α结合位点，这些结合位点中的一部分在体内被HNF4α占据。结论：HNF4α是哺乳动物结肠发育所必需的转录因子，调节杯状细胞的成熟，是控制正常结肠功能和上皮细胞分化的基因表达所必需的。
Background & Aims: Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a transcription factor that has been shown to be required for hepatocyte differentiation and development of the liver. It has also been implicated in regulating expression of genes that act in the epithelium of the lower gastrointestinal tract. This implied that HNF4 alpha might be required for development of the gut. Methods: Mouse embryos were generated in which Hnf4a was ablated in the epithelial cells of the fetal colon by using Cre-loxP technology. Embryos were examined by using a combination of histology, immunohistochemistry, DNA microarray, reverse-transcription polymerase chain reaction, electrophoretic mobility shift assays, and chromatin immunoprecipitation analyses to define the consequences of loss of HNF4 alpha on colon development. Results: Embryos were recovered at E18.5 that lacked HNF4 alpha in their colons. Although early stages of colonic development occurred, HNF4 alpha-null colons failed to form normal crypts. In addition, goblet-cell maturation was perturbed and expression of an array of genes that encode proteins with diverse roles in colon function was disrupted. Several genes whose expression in the colon was dependent on HNF4 alpha contained HNF4 alpha-binding sites within putative transcriptional regulatory regions and a subset of these sites were occupied by HNF4 alpha in vivo. Conclusions: HNF4 alpha is a transcription factor that is essential for development of the mammalian colon, regulates goblet-cell maturation, and is required for expression of genes that control normal colon function and epithelial cell differentiation.