UCSF

Beta-catenin, a cellular adhesion protein, plays a central role in the canonical Wnt-signaling pathway. Wnt ligand binding enables Beta-catenin to enter the nucleus where it interacts with TCF/Lef transcriptional coactivators to drive expression of Wnt-responsive target genes. However, in the absence of Wnt ligand, free cytoplasmic Beta-catenin is targeted for degradation via ubiquitylation sites encoded by the third exon of the Beta-catenin gene.

Previous studies utilizing Wnt-responsive reporter mice have demonstrated that the canonical Wnt pathway is active within the early pancreatic epithelium. Moreover, deletion of Beta-catenin within the murine pancreas results in a variety of phenotypes, including organ hypoplasia and a reduction in endocrine mass. In this study, we have used the Beta-cat^active mouse to activate pancreatic Wnt signaling in a variety of biological contexts.

The third exon of the Beta-catenin gene is flanked by lox P sites in these Beta-cat^active mice. Therefore, Cre-recombinase mediated excision of this exon results in a constituitive activation of the Beta-catenin signaling pathway, since the protein can no longer be targeted for degradation.

Strong activation of Beta-catenin by e10.5 within the pancreatic epithelium results in near complete pancreas ablation and neonatal lethality in PdxCre^early Beta-cat^active mice. This is preceded by a cell autonomous loss of Pdx1, a decrease in FGF10 signaling, and an increase in Hedgehog (Hh) Hh signaling. Conversely, PdxCre^late Beta-cat^active mice exhibit a nearly five fold increase in pancreas mass due to acinar cell proliferation. This dramatic difference in phenotype is the result of a delay in the onset of Cre expression in the PdxCre^late mouse.

Increased pancreatic mass is also seen in p48 Cre Beta-cat^active mice. However, unlike the PdxCre^late

Beta-cat^active mouse strain, these animals develop large pancreatic lesions that resemble human pseudopapillary tumors. These lesions may originate in the pancreatic ducts, a cell type that is targeted efficiently by the p48 Cre, but not the PdxCre^late strain.

Finally, we show that activation of Beta-catenin is sufficient to induce Beta-cell proliferation and expansion of Beta-cell mass. This finding may be of therapeutic importance in the development of cell based therapies for Type I diabetes.