Article
- The EMBO Journal (2004) 23, 1657 - 1668
- doi:10.1038/sj.emboj.7600160
Published online: 18 March 2004
Subject Category:
A transcriptional network in polycystic kidney disease
Lionel Gresh1,a, Evelyne Fischer1,a, Andreas Reimann1,a, Myriam Tanguy2, Serge Garbay1, Xinli Shao3, Thomas Hiesberger3, Laurence Fiette2, Peter Igarashi3, Moshe Yaniv1 and Marco Pontoglio1
- Unité Expression Génétique et Maladies/CNRS URA 1644, Département de Biologie du Développement, Institut Pasteur, Paris, France
- Unité de Recherche et d'Expertise en Histotechnologie et Pathologie, Institut Pasteur, Paris, France
- Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
Correspondence to:
Marco Pontoglio, Unité Expression Génétique et Maladies/CNRS URA 1644, Département de Biologie du Développement, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France. Tel.: +33 1 45 68 85 14; Fax: +33 1 40 61 30 33; E-mail: marcop@pasteur.fr
aThese authors contributed equally to this work
Received 11 November 2003; Accepted 13 February 2004
Abstract
Mutations in cystic kidney disease genes represent a major genetic cause of end-stage renal disease. However, the molecular cascades controlling the expression of these genes are still poorly understood. Hepatocyte Nuclear Factor 1
(HNF1) is a homeoprotein predominantly expressed in renal, pancreatic and hepatic epithelia. We report here that mice with renal-specific inactivation of HNF1 develop polycystic kidney disease. We show that renal cyst formation is accompanied by a drastic defect in the transcriptional activation of Umod, Pkhd1 and Pkd2 genes, whose mutations are responsible for distinct cystic kidney syndromes. In vivo chromatin immunoprecipitation experiments demonstrated that HNF1 binds to several DNA elements in murine Umod, Pkhd1, Pkd2 and Tg737/Polaris genomic sequences. Our results uncover a direct transcriptional hierarchy between HNF1 and cystic disease genes. Interestingly, most of the identified HNF1 target gene products colocalize to the primary cilium, a crucial organelle that plays an important role in controlling the proliferation of tubular cells. This may explain the increased proliferation of cystic cells in MODY5 patients carrying autosomal dominant mutations in HNF1.
Keywords:
- cilium,
- cysts,
- HNF1,
- MODY5,
- proliferation
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