title: β-catenin causes renal dysplasia via upregulation of Tgfβ2 and Dkk1.
abstract: Renal dysplasia, defined by defective ureteric branching morphogenesis and nephrogenesis, is the major cause of renal failure in infants and children. Here, we define a pathogenic role for a β-catenin-activated genetic pathway in murine renal dysplasia. Stabilization of β-catenin in the ureteric cell lineage before the onset of kidney development increased β-catenin levels and caused renal aplasia or severe hypodysplasia. Analysis of gene expression in the dysplastic tissue identified downregulation of genes required for ureteric branching and upregulation of Tgfβ2 and Dkk1. Treatment of wild-type kidney explants with TGFβ2 or DKK1 generated morphogenetic phenotypes strikingly similar to those observed in mutant kidney tissue. Stabilization of β-catenin after the onset of kidney development also caused dysplasia and upregulation of Tgfβ2 and Dkk1 in the epithelium. Together, these results demonstrate that elevation of β-catenin levels during kidney development causes dysplasia.
authors: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
authors: Darren
authors: D
authors: Bridgewater
authors: Valeria
authors: V
authors: Di Giovanni
authors: Jason E
authors: JE
authors: Cain
authors: Brian
authors: B
authors: Cox
authors: Madis
authors: M
authors: Jakobson
authors: Kirsi
authors: K
authors: Sainio
authors: Norman D
authors: ND
authors: Rosenblum
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology* / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis / Q000502:physiology; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology; D053781:Transforming Growth Factor beta2 / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D014513:Ureter / Q000002:abnormalities / Q000196:embryology / Q000503:physiopathology; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053781:Transforming Growth Factor beta2; D051153:Wnt Proteins; D051176:beta Catenin