Stromally Expressed β-Catenin Modulates Wnt9b Signaling in the Ureteric Epithelium

The mammalian kidney undergoes cell interactions between the epithelium and mesenchyme to form the essential filtration unit of the kidney, termed the nephron. A third cell type, the kidney stroma, is a population of fibroblasts located in the kidney capsule, cortex and medulla and is ideally located to affect kidney formation. We found beta-catenin, a transcriptional co-activator, is strongly expressed in distinctive intracellular patterns in the capsular, cortical, and medullary renal stroma. We investigated beta-catenin function in the renal stroma using a conditional knockout strategy that genetically deleted beta-catenin specifically in the renal stroma cell lineage (beta-cats(-/-)). beta-cats(-/-) mutant mice demonstrate marked kidney abnormalities, and surprisingly we show beta-catenin in the renal stroma is essential for regulating the condensing mesenchyme cell population. We show that the population of induced mesenchyme cells is significantly reduced in beta-cats(-/-) mutants and exhibited decreased cell proliferation and a specific loss of Cited 1, while maintaining the expression of other essential nephron progenitor proteins. Wnt9b, the key signal for the induction of nephron progenitors, was markedly reduced in adjacent ureteric epithelial cells in beta-cats(-/-). Analysis of Wnt9b-dependent genes in the neighboring nephron progenitors was significantly reduced while Wnt9b-independent genes remained unchanged. In contrast mice overexpressing beta-catenin exclusively in the renal stroma demonstrated massive increases in the condensing mesenchyme population and Wnt9b was markedly elevated. We propose that beta-catenin in the renal stroma modulates a genetic program in ureteric epithelium that is required for the induction of nephron progenitors.