Wnt signaling regulates pancreatic β cell proliferation

There is widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet cells. Wnt signaling is an important regulator of organ growth and cell fates, and genes encoding Wnt-signaling factors are expressed in the pancreas. However, it is unclear whether Wnt s...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-04, Vol.104 (15), p.6247-6252
Main Authors: Rulifson, Ingrid C, Karnik, Satyajit K, Heiser, Patrick W, ten Berge, Derk, Chen, Hainan, Gu, Xueying, Taketo, Makoto M, Nusse, Roel, Hebrok, Matthias, Kim, Seung K
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cell cycle
Cell cycle proteins
Cell growth
Cell Proliferation
Cyclin D2
Cyclins
Cyclins - metabolism
Homeobox Protein PITX2
Homeodomain Proteins - metabolism
Immunohistochemistry
Insulin
Insulin-Secreting Cells - physiology
Islet cells
Islets of Langerhans
Mice
Mice, Mutant Strains
Pancreas
Pancreatic cells
Regulator genes
Signal Transduction - physiology
Transcription Factors - metabolism
Wnt Proteins - metabolism
Wnt3 Protein
Wnt3A Protein
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Summary:There is widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet cells. Wnt signaling is an important regulator of organ growth and cell fates, and genes encoding Wnt-signaling factors are expressed in the pancreas. However, it is unclear whether Wnt signaling regulates pancreatic islet proliferation and differentiation. Here we provide evidence that Wnt signaling stimulates islet β cell proliferation. The addition of purified Wnt3a protein to cultured β cells or islets promoted expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of β cell cycle progression, and led to increased β cell proliferation in vitro. Conditional pancreatic β cell expression of activated β-catenin, a crucial Wnt signal transduction protein, produced similar phenotypes in vivo, leading to β cell expansion, increased insulin production and serum levels, and enhanced glucose handling. Conditional β cell expression of Axin, a potent negative regulator of Wnt signaling, led to reduced Pitx2 and Cyclin D2 expression by β cells, resulting in reduced neonatal β cell expansion and mass and impaired glucose tolerance. Thus, Wnt signaling is both necessary and sufficient for islet β cell proliferation, and our study provides previously unrecognized evidence of a mechanism governing endocrine pancreas growth and function.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0701509104