Cell growth

Pancreatic β Cell Proliferation Is Stimulated by Wnt Signaling

Science's STKE  17 Apr 2007:
Vol. 2007, Issue 382, pp. tw130
DOI: 10.1126/stke.3822007tw130

Both type 1 and type 2 diabetes result from a loss of pancreatic β cell mass. There is considerable interest, therefore, in understanding the mechanisms responsible for β cell proliferation. Previous studies have shown that various components of the Wnt signaling pathway are found in the pancreas and that dysregulation of this pathway can result in reduced islet mass, but the exact mechanisms involved are unknown. Wnts are small proteins that signal though cell surface receptors called Frizzleds, leading to the stabilization and accumulation of β-catenin. This protein then translocates to the nucleus, where it interacts with transcription factors to control the transcription of target genes. Rulifson et al. investigated this link between the Wnt pathway and β cell proliferation by treating cultured mouse pancreatic islets with purified Wnt3a. Immunohistochemical analysis demonstrated increased amounts of Ki67, a marker of cell proliferation. Treatment of islets with Wnt3a also increased the abundance of the mRNAs for the transcription factor Pitx2, a known downstream target of β-catenin, and cyclin D2, a protein involved in control of the cell cycle. Chromatin immunoprecipitation assays revealed that Wnt3a directed the association of Pitx2 with the cyclin D2 gene. Mice with pancreas-specific expression of a constitutively active form of β-catenin had increased β cell proliferation and higher serum insulin levels than did wild-type mice. In contrast, transgenic mice with pancreas-specific inducible expression of Axin, a negative regulator of β-catenin, had reduced islet mass, lower insulin production, and lower abundance of Pitx2 and cyclin D2 than did wild-type mice. This study provides mechanistic evidence of the importance of Wnt signaling for β cell proliferation.

I. C. Rulifson, S. K. Karnik, P. W. Heiser, D. ten Berge, H. Chen, X. Gu, M. M. Taketo, R. Nusse, M. Hebrok, S. K. Kim, Wnt signaling regulates pancreatic β cell proliferation. Proc. Natl. Acad. Sci. USA 104, 6247-6252 (2007). [Abstract] [Full Text]