β-Catenin Causes Renal Dysplasia via Upregulation of Tgfβ2 and Dkk1

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 beta-catenin-activated genetic pathway in murine renal dysplasia. Stabilization of beta-catenin in the ureteric cell lineage before the onset of kidney development increased beta-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 Tgf beta 2 and Dkk1. Treatment of wild-type kidney explants with TGF beta 2 or DKK1 generated morphogenetic phenotypes strikingly similar to those observed in mutant kidney tissue. Stabilization of p-catenin after the onset of kidney development also caused dysplasia and upregulation of Tgf beta 2 and Dkk1 in the epithelium. Together, these results demonstrate that elevation of p-catenin levels during kidney development causes dysplasia.