Canonical Wnt signalling, mediated by Wnt9b, Wnt4 and others, plays a crucial role in the early induction and subsequent conversion of the metanephric mesenchyme to tubular epithelial cells - genetic deletion of Wnt9b or Wnt4 results in renal agenesis. Conversely, persistent activation of the canonical Wnt signalling cascade is cystogenic; progressive destruction of the normal kidney structure results from a constitutively active form of ß-catenin or depletion of the APC tumor suppressor.

Since ß-catenin is involved in multiple cellular programs, its inactivation affects more than canonical Wnt signalling during mouse renal development. Preliminary work in project P5 (R. Grosschedl) has resulted in a LEF1 mutant that selectively binds cytoplasmic and nuclear ß-catenin, but lacks the DNA-binding domain and nuclear localization signal of Lef1. This LEF1 mutant inhibits the TCF/LEF-dependent activation of Wnt target genes and causes renal agenesis without disrupting the formation of adherens junctions at the plasma membrane. Studies with LEF1-mutant mice will clearly delineate the role of canonical Wnt signalling during renal embryogenesis and cystogenesis. Recent data indicates that the cilium regulates canonical Wnt signalling.  Project P6 (W. Kühn) will use an in vitro micro-chamber system to model ciliary signalling and analyse how ciliary defects affect signalling cascades involved in renal development. In preliminary studies, P6 uncovered that flow-dependent ciliary signalling regulates the cell size through inhibition of mTOR signalling. The micro-chamber may therefore provide a novel approach to analyse ciliary mTOR control and test pharmacological interventions aimed to retard cyst growth in vitro. This project will also evaluate the function of newly identified candidate molecules from project P1 and P2 during flow-dependent ciliary signalling.