| During kidney development, there is a switch from predominantly canonical to non-canonical WNT signalling. This switch transitions the developing kidney from a state of active proliferation to that of terminal differentiation. The current belief is that a defect in this switch is an underlying mechanism in the pathogenesis of autosomal dominant polycystic kidney disease. We first hypothesized that a failure to suppress canonical WNT signalling would lead to cyst formation and following this line of reasoning, crossed a β-catenin transcriptional activity reporter mouse to mice with mutations in Pkd1 or Pkd2. We found no aberrant canonical WNT signalling in the epithelial cells lining the cysts and concluded that a failure to restrict β-catenin transcriptional activity does not occur in autosomal dominant polycystic kidney disease. We next examined if an inability to activate a non-canonical WNT signalling pathway, specifically the WNT-calcium pathway, contributes to cystogenesis. WNT-calcium signalling was not previously characterized in the developing kidney, so we first established cell culture, organ culture, and in vivo systems to study the pathway in a normal developmental context. We showed that pathway activity peaks from embryonic day (E)13 to E16 and is located in the nephrogenic zone of E16 kidneys. We further demonstrated that activation of the WNT-calcium pathway in vitro restricts cell motility, an important process during mesenchymal cell condensation to form the renal vesicle. To assess the role of WNT-calcium signalling in autosomal dominant polycystic kidney disease, we crossed an NFAT transcriptional activity reporter mouse to mice with mutations in Pkd2 and found that pathway activity is significantly reduced in cystic kidneys. Taken together, this study supports the hypothesis of a developmental switch between canonical and non-canonical WNT signalling during normal kidney development and suggests that a failure to fully activate the WNT-calcium pathway may be a contributing factor in the pathogenesis of autosomal dominant polycystic kidney disease. |
