Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium
Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium
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DOI：
10.1242/dev.044420
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发表时间：
2010-05-01
期刊：
影响因子：
4.6
通讯作者：
Pontoglio, Marco
中科院分区：
文献类型：
--
作者：
D'Angelo, Anna;Bluteau, Olivier;Pontoglio, Marco
肠上皮是一个复杂的系统，其特征在于大量和连续的细胞更新和分化。在这种情况下，细胞类型特异性转录因子被认为通过调节特定的转录网络和信号通路发挥关键作用。hnf 1 α和β是在包括肠道在内的几种上皮细胞中表达的密切相关的非典型同源异型蛋白转录因子。使用条件性灭活系统，我们产生了小鼠，其中Hnf 1b在野生型或Hnf 1a（-/-）遗传背景的肠上皮中特异性灭活。而单独的Hnf 1a或Hnf 1b的失活不会导致任何主要的肠道功能障碍，这两个基因的伴随失活导致致命的表型。双突变动物有缺陷的分化和细胞命运的承诺。所有分化细胞类型（肠上皮细胞和分泌细胞）的标志物的表达水平均受到影响。此外，杯状细胞的数量增加，而成熟的潘氏细胞缺失。在分子水平上，我们发现Hnf 1 α和β在Notch通路的上游起作用，直接控制两个关键组分的表达：Jag 1和Atoh 1。我们证明了双突变小鼠存在肠道水吸收缺陷，并且Hnf 1 α和β直接控制Slc 26 a3的表达，Slc 26 a3是一种基因，其突变与人类患者的氯化物腹泻相关。我们的研究确定了Hnf 1转录因子的新的直接靶基因，并表明它们在确定细胞命运和控制肠上皮细胞的末端功能方面发挥着至关重要的作用。
The intestinal epithelium is a complex system characterized by massive and continuous cell renewal and differentiation. In this context, cell-type-specific transcription factors are thought to play a crucial role by modulating specific transcription networks and signalling pathways. Hnf1 alpha and beta are closely related atypical homeoprotein transcription factors expressed in several epithelia, including the gut. With the use of a conditional inactivation system, we generated mice in which Hnf1b is specifically inactivated in the intestinal epithelium on a wild-type or Hnf1a(-/-) genetic background. Whereas the inactivation of Hnf1a or Hnf1b alone did not lead to any major intestinal dysfunction, the concomitant inactivation of both genes resulted in a lethal phenotype. Double-mutant animals had defective differentiation and cell fate commitment. The expression levels of markers of all the differentiated cell types, both enterocytes and secretory cells, were affected. In addition, the number of goblet cells was increased, whereas mature Paneth cells were missing. At the molecular level, we show that Hnf1 alpha and beta act upstream of the Notch pathway controlling directly the expression of two crucial components: Jag1 and Atoh1. We demonstrate that the double-mutant mice present with a defect in intestinal water absorption and that Hnf1 alpha and beta directly control the expression of Slc26a3, a gene whose mutations are associated with chloride diarrhoea in human patients. Our study identifies new direct target genes of the Hnf1 transcription factors and shows that they play crucial roles in both defining cell fate and controlling terminal functions in the gut epithelium.