These models have uncovered essential roles for canonical Wnt SP600125 signaling in bone, hair, intestine, blood, and cancer. An emerging theme from these studies is that many biological processes are acutely sensitive to the strength of canonical Wnt signaling. This tight regulation of canonical Wnt signaling is essential for kidney development. During the initial stages of kidney formation, Wnt9b is secreted from the ureteric bud and signals to progenitor cells in the cap mesenchyme to induce nephron differentiation. Treatment with lithium chloride or activation of b-catenin can induce nephron differentiation in the absence of the ureteric bud and Wnt9b, suggesting that an increase in canonical Wnt signaling is sufficient for this inductive event. Some cap mesenchyme cells proliferate to maintain the progenitor cells that are required for subsequent iterations of this process. This balance between progenitor maintenance and the induction of differentiation is of paramount importance to ensure that the kidney forms the full complement of nephrons. Several factors expressed in the cap mesenchyme have been shown to antagonize Wnt-stimulated differentiation including the transcription factor Six2. Deletion of Six2 results in ectopic differentiation, depletion of cap mesenchyme progenitors, and kidney agenesis. Although the exact mechanism is not yet known, a hypothesis has been proposed whereby high levels of canonical Wnt signaling drive the commitment to differentiation whereas high Six2 activity in the same cells maintains the progenitor fate. We have created a new mouse model to conditionally overexpress Wnt9b to activate the canonical Wnt signaling pathway. We have used this model to test whether increased Wnt9b activity is sufficient to disrupt the balance between progenitors and differentiation in the cap mesenchyme. A second site where both Six2 activity and Wnt signaling play an important role is the pyloric sphincter. The pyloric sphincter is formed at the distal end of the stomach and functions as a valve to enable proper digestion of food prior to its entry into the duodenum. Dysfunction of the sphincter can result in reflux of duodenal contents into the stomach posing an increased risk of gastric metaplasia and cancer. This region is also the site of congenital anomalies including the rare disorder primary duodenogastric reflux and the more common birth defect pyloric stenosis. Six2 deficiency leads to agenesis of the pyloric sphincter and antagonizing Wnt activity with Sfrp1 and Sfrp2 is required to pattern the stomach. This led us to hypothesize that canonical Wnt activity must be tightly regulated in the pylorus similar to what has been proposed in the kidney. To test this we have used Six2-cre to activate the Wnt9b transgene in Six2 expressing domains in kidney and stomach. The conditional Wnt9b transgenic allele reported here expresses Wnt9b and GFP when activated by cre recombinase. It is biologically active and capable of rescuing kidney formation in Wnt9b2/2 embryos. Overexpression of Wnt9b in the kidney ureteric bud is capable of inducing genes associated with differentiation of cap mesenchyme, but does not undergo mesenchymal-to-epithelial transition to produce morphologically distinct vesicle structures. Wnt9b transgene activation in Six2-positive cells causes kidney cysts and a transformation of the distal stomach regions into proximal stomach fate. Suggests that these strains represent an allelic series that should be valuable for modulating canonical Wnt signaling in other tissues.