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

doi:10.1128/MCB.00939-09

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Molecular and Cellular Biology, December 2009, p. 6294-6308, Vol. 29, No. 23
0270-7306/09/$08.00+0 doi:10.1128/MCB.00939-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hepatocyte Nuclear Factor 4 ${alpha}$ , a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium

Anne-Laure Cattin,¹^,2^,3 Johanne Le Beyec,¹^,2^,3 Frederick Barreau,⁴ Susan Saint-Just,¹^,2^,3^,5 Anne Houllier,¹^,2^,3 Frank J. Gonzalez,⁶ Sylvie Robine,⁷ Martine Pinçon-Raymond,¹^,2^,3 Philippe Cardot,¹^,2^,3 Michel Lacasa,¹^,2^,3 and Agnès Ribeiro¹^,2^,3^*

Centre de Recherche des Cordeliers, Université Pierre et Marie Curie—Paris 6, UMRS 872, Paris F-75006, France,¹ INSERM, U872, Paris F-75006, France,² Université Paris Descartes, UMRS 872, Paris F-75006, France,³ Laboratoire de Pharmacologie Cellulaire et Moléculaire, Ecole Pratique des Hautes Etudes, Paris F-75006, France,⁴ Morphogenesis and Intracellular Signaling, UMR 144, Institut Curie-CNRS, Paris, France,⁵ Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,⁶ UMR-S843 INSERM, Université Paris Diderot, Service de Gastroentérologie, Hôpital R. Debré, AP-HP, Paris, France⁷

Received 17 July 2009/ Returned for modification 20 August 2009/ Accepted 17 September 2009

Hepatocyte nuclear factor 4 ${alpha}$ (HNF-4 ${alpha}$ ) is a transcription factorwhich is highly expressed in the intestinal epithelium fromduodenum to colon and from crypt to villus. The homeostasisof this constantly renewing epithelium relies on an integratedcontrol of proliferation, differentiation, and apoptosis, aswell as on the functional architecture of the epithelial cells.In order to determine the consequences of HNF-4 ${alpha}$ loss in theadult intestinal epithelium, we used a tamoxifen-inducible Cre-loxPsystem to inactivate the Hnf-4a gene. In the intestines of adultmice, loss of HNF-4 ${alpha}$ led to an increased proliferation in cryptsand to an increased expression of several genes controlled bythe Wnt/β-catenin system. This control of the Wnt/β-cateninsignaling pathway by HNF-4 ${alpha}$ was confirmed in vitro. Cell lineagewas affected, as indicated by an increased number of gobletcells and an impairment of enterocyte and enteroendocrine cellmaturation. In the absence of HNF-4 ${alpha}$ , cell-cell junctions weredestabilized and paracellular intestinal permeability increased.Our results showed that HNF-4 ${alpha}$ modulates Wnt/β-catenin signalingand controls intestinal epithelium homeostasis, cell function,and cell architecture. This study indicates that HNF-4 ${alpha}$ regulatesthe intestinal balance between proliferation and differentiation,and we hypothesize that it might act as a tumor suppressor.

* Corresponding author. Mailing address: UMRS 872, 15 rue de l'école de médecine, 75006 Paris, France. Phone: 33 1 42 34 69 18. Fax: 33 1 43 25 16 15. E-mail: agnes.ribeiro-pillet{at}crc.jussieu.fr

Published ahead of print on 5 October 2009.

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

Hepatocyte Nuclear Factor 4 ${alpha}$ , a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium