β-Catenin Overexpression in the Metanephric Mesenchyme Leads to Renal Dysplasia Genesis via Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Renal dysplasia, a developmental disorder characterized by defective ureteric branching morphogenesis and nephrogenesis, ranks as one of the major causes of renal failure among the pediatric population. Herein, we demonstrate that the levels of activated beta-catenin are elevated in the nuclei of ureteric, stromal, and mesenchymal cells within dysplastic human kidney tissue. By using a conditional mouse model of mesenchymal beta-catenin overexpression, we identify two novel signaling pathways mediated by beta-catenin in the development of renal dysplasia. First, the overexpression of beta-catenin within the metanephric mesenchyme Leads to ectopic and disorganized branching morphogenesis caused by beta-catenin directly binding Tcf/Lef consensus binding sites in the Gdnf promoter and up-regulating Gdnf transcription. Second, beta-catenin overexpression in the metanephric mesenchyme leads to elevated Levels of transcriptionally active beta-catenin in the ureteric epithelium. Interestingly, this increase of beta-catenin mediated transcription results from a novel Ret/beta-catenin signaling pathway. Consistent with these findings, analysis of human dysplastic renal tissue demonstrates that undifferentiated mesenchymal cells expressing high levels of beta-catenin also express increased GDNF. Furthermore, dysplastic ureteric tubules that were surrounded by high levels of GONE also exhibited increased levels of activated beta-catenin. Together, these data support a model in which the elevation of beta-catenin in the metanephric mesenchyme results in cell-autonomous and non-cell-autonomous events that lead to the genesis of renal dysplasia.