Cadherin Adhesion Complexes Direct Cell Aggregation in the Epithelial Transition of Wnt-Induced Nephron Progenitor Cells

In the developing mammalian kidney, nephron formation is initiated by a subset of nephron progenitor cells (NPCs). Wnt input activates a {beta}-catenin (Ctnnb1)-driven, transcriptional nephrogenic program. In conjunction, induced mesenchymal NPCs transition through a pre-tubular aggregate to an epithelial renal vesicle, the precursor for each nephron. How this critical mesenchymal-to-epithelial transition (MET) is regulated is unclear. In an in vitro mouse NPC culture model, activation of the Wnt pathway results in the aggregation of induced NPCs into closely-packed, cell clusters. Genetic removal of {beta}-catenin resulted in a failure of both Wnt pathway-directed transcriptional activation and the formation of aggregated cell clusters. Modulating extracellular Ca2+ levels showed cell-cell contacts were Ca2+-dependent, suggesting a role for cadherin (Cdh)-directed cell adhesion. Molecular analysis identified Cdh2, Cdh4 and Cdh11 in uninduced NPCs and the up-regulation of Cdh3 and Cdh4 accompanying the Wnt pathway-induced MET. Genetic removal of all four cadherins, and independent removal of -catenin, which couples Cdh-{beta}-catenin membrane complexes to the actin cytoskeleton, abolished cell aggregation in response to Wnt pathway activation. However, the {beta}-catenin driven inductive transcriptional program was unaltered. Together with the accompanying paper (Bugacov et al., submitted), these data demonstrate that distinct cellular activities of {beta}-catenin - transcriptional regulation and cell adhesion - combine in the mammalian kidney programs generating differentiated epithelial nephron precursors from mesenchymal nephron progenitors. Summary statementOur study highlights the role of Wnt-{beta}-catenin pathway regulation of cadherin-mediated cell adhesion in the mesenchymal to epithelial transition of induced nephron progenitor cells.