Beta-Catenin Causes Renal Dysplasia Via Upregulation Of Tgf Beta 2 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.