This is supported by the expression domains of these genes since a canonical Wnt signaling reporter exhibits high activity only in the forestomach, and Six2 is confined to the distal stomach and pylorus. These results describe the creation of a new mouse model that conditionally activates canonical Wnt signaling. The Wnt9b transgene is inducible upon exposure to cre recombinase and expresses GFP as a marker of induction. It also retains full biological activity since it can rescue Wnt9b2/2 phenotypes in the kidney. These mice have been maintained in our colony for over a year and induce Wnt9b expression upon breeding to multiple different cre strains. We have utilized this novel strain to activate Wnt signaling in Six2-positive cells and found deleterious effects in the kidney and the stomach. In the kidney, Wnt9b is secreted from the ureteric bud epithelium to induce the adjacent cap mesenchyme progenitor cells to initiate differentiation. In support of this model, our in vivo gain-of-function studies show that Wnt9b upregulates early markers of renal vesicle differentiation such as Wnt4, Fgf8 and Pax8. However, even though renal vesicle genes are induced by the Wnt9b transgene, we did not observe morphological evidence of increased or ectopic renal vesicle formation, as reported for Six2 mutants. In addition to a Wnt inductive signal, factors that maintain the renal progenitor pool must also be downregulated to fully elicit renal vesicle formation. Six2 expression was not altered in our Wnt9b transgenic and may thus explain why the increase in Wnt9b did not result in ectopic renal vesicles. Ectopic induction of renal vesicle markers is induced by activation of b-catenin in Six2-positive metanephric mesenchyme using the stabilized b-catenin allele, therefore, the difference between these two gain-of-function experiments may relate to the degree to which they activate canonical Wnt activity. In addition, it is likely that activation of canonical signaling by Wnt9b in metanephric mesenchyme induces feedback inhibition, as noted in other Wnt responsive tissues, thereby preventing induction of the full differentiation program. Recent data support this idea of feedback inhibition since Wnt9b/b-catenin signaling is required not only for the differentiation of metanephric mesenchyme, but paradoxically the same signal is also required for maintenance or expansion of the renal progenitor pool. We speculate that the stabilized b-catenin, acting downstream in the pathway, may bypass these regulatory mechanisms. These possibilities could be tested in future studies in that compare downstream gene activation in renal progenitor cells using the Wnt9b transgene and stabilized b-catenin gain-of-function mice. Perturbations in the canonical Wnt signaling pathway have been shown to be important in the pathogenesis of renal cystic disease. Transgenic expression of a stabilized b-catenin or deficiency of APC in renal tubular epithelia leads to renal cystic disease, supporting the conclusion that ectopic canonical Wnt signaling is sufficient for cystogenesis. Renal failure and cystic dilatation in Six2-cretg/+, Wnt9btg/+ double heterozygotes further supports the hypothesis that upregulated canonical Wnt signaling causes cysts. Disruption of non-canonical Wnt signaling pathway is also important in renal cyst formation. Thus, it is possible that cyst formation in our model is not simply due to activation of canonical signaling, but is the result of disruption of the ICI 182780 relative balance between canonical and non-canonical signaling.