Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium

被引:117
作者
Cattin, Anne-Laure [1 ,2 ,3 ]
Le Beyec, Johanne [1 ,2 ,3 ]
Barreau, Frederick [4 ]
Saint-Just, Susan [1 ,2 ,3 ,5 ]
Houllier, Anne [1 ,2 ,3 ]
Gonzalez, Frank J. [6 ]
Robine, Sylvie [7 ]
Pincon-Raymond, Martine [1 ,2 ,3 ]
Cardot, Philippe [1 ,2 ,3 ]
Lacasa, Michel [1 ,2 ,3 ]
Ribeiro, Agnes [1 ,2 ,3 ]
机构
[1] Univ Paris 06, Ctr Rech Cordeliers, UMRS 872, F-75006 Paris, France
[2] INSERM, U872, F-75006 Paris, France
[3] Univ Paris 05, UMRS 872, F-75006 Paris, France
[4] EPHE, Pharmacol Cellulaire & Mol Lab, F-75006 Paris, France
[5] Inst Curie, CNRS, UMR Morphogenesis & Intracellular Signaling 144, F-75231 Paris, France
[6] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
[7] Univ Paris Diderot, Hop Robert Debre, AP HP, INSERM,Serv Gastroenterol,UMR S843, Paris, France
关键词
A-IV GENE; BETA-CATENIN; POLY(ADP-RIBOSE) POLYMERASE-1; TIGHT JUNCTIONS; E-CADHERIN; EXPRESSION; RECEPTOR; PROLIFERATION; TRANSCRIPTION; CRYPT;
D O I
10.1128/MCB.00939-09
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hepatocyte nuclear factor 4 alpha (HNF-4 alpha) is a transcription factor which is highly expressed in the intestinal epithelium from duodenum to colon and from crypt to villus. The homeostasis of this constantly renewing epithelium relies on an integrated control of proliferation, differentiation, and apoptosis, as well as on the functional architecture of the epithelial cells. In order to determine the consequences of HNF-4 alpha loss in the adult intestinal epithelium, we used a tamoxifen-inducible Cre-loxP system to inactivate the Hnf-4a gene. In the intestines of adult mice, loss of HNF-4 alpha led to an increased proliferation in crypts and to an increased expression of several genes controlled by the Wnt/beta-catenin system. This control of the Wnt/beta-catenin signaling pathway by HNF-4 alpha was confirmed in vitro. Cell lineage was affected, as indicated by an increased number of goblet cells and an impairment of enterocyte and enteroendocrine cell maturation. In the absence of HNF-4 alpha, cell-cell junctions were destabilized and paracellular intestinal permeability increased. Our results showed that HNF-4 alpha modulates Wnt/beta-catenin signaling and controls intestinal epithelium homeostasis, cell function, and cell architecture. This study indicates that HNF-4 alpha regulates the intestinal balance between proliferation and differentiation, and we hypothesize that it might act as a tumor suppressor.
引用
收藏
页码:6294 / 6308
页数:15
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