Conditional Expression of Wnt9b in Six2-Positive Cells Disrupts Stomach and Kidney Function

During kidney development, canonical Wnt signaling activates differentiation, while the transcription factor Six2 maintains the progenitor pool. These opposing signals help to regulate nephron formation and ensure the full complement of nephrons are formed. Since these two factors control differing fates in kidney mesenchyme, we hypothesized that overexpression of Wnt9b in Six2-expressing cells would disrupt kidney formation and may alter cell differentiation decisions in other tissues. We created a transgenic mouse that conditionally expressed the canonical Wnt ligand in the developing kidney, Wnt9b. The transgene is activated by cre recombinase and expresses GFP. We first tested its biological activity using Hoxb7-cre and found that transgenic Wnt9b was capable of inducing differentiation genes and of rescuing kidney development in Wnt9b(-/-) homozygous deficient mice. In contrast, expression of Wnt9b in cells using Six2-cre caused gastrointestinal distress and severe renal failure in adult mice. Transgenic kidneys had numerous cystic tubules and elevated creatinine values (0.652 +/- 0.044) compared to wild-type mice (0.119 +/- 0.002). These animals also exhibited a malformed pyloric sphincter, duodenogastric reflux, and a transformation of the distal stomach into proximal fate. The gene expression changes observed for the Wnt9b:EGFP transgene were compared to a stabilized beta-catenin allele to determine that Wnt9b is activating the canonical Wnt pathway in the tissues analyzed. These results demonstrate that expression of Wnt9b in Six2-positive cells disrupts cell fate decisions in the kidney and the gastrointestinal tract.