title: A transcriptional network in polycystic kidney disease.
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 1beta (HNF1beta) is a homeoprotein predominantly expressed in renal, pancreatic and hepatic epithelia. We report here that mice with renal-specific inactivation of HNF1beta 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 HNF1beta binds to several DNA elements in murine Umod, Pkhd1, Pkd2 and Tg737/Polaris genomic sequences. Our results uncover a direct transcriptional hierarchy between HNF1beta and cystic disease genes. Interestingly, most of the identified HNF1beta 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 HNF1beta.
authors.affiliation: Unité Expression Génétique et Maladies/CNRS URA 1644, Département de Biologie du Développement, Institut Pasteur, Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Gresh
authors.forename: Evelyne
authors.initials: E
authors.lastname: Fischer
authors.forename: Andreas
authors.initials: A
authors.lastname: Reimann
authors.forename: Myriam
authors.initials: M
authors.lastname: Tanguy
authors.forename: Serge
authors.initials: S
authors.lastname: Garbay
authors.forename: Xinli
authors.initials: X
authors.lastname: Shao
authors.forename: Thomas
authors.initials: T
authors.lastname: Hiesberger
authors.forename: Laurence
authors.initials: L
authors.lastname: Fiette
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
authors.forename: Moshe
authors.initials: M
authors.lastname: Yaniv
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002923:Cilia / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000473:pathology / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009088:Mucoproteins / Q000235:genetics / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D050396:TRPP Cation Channels; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014513:Ureter / Q000473:pathology; D058949:Uromodulin
chemical_list: D004268:DNA-Binding Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D008565:Membrane Proteins; D009088:Mucoproteins; D011956:Receptors, Cell Surface; D050396:TRPP Cation Channels; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D058949:Uromodulin; C496495:HNF1B protein, human; C496496:Hnf1b protein, mouse; C484365:Pkhd1 protein, mouse; C490898:Tg737Rpw protein, mouse; C548612:UMOD protein, human; C548613:Umod protein, mouse