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Published online on April 2, 2007, 10.1073/pnas.0701509104 OPEN ACCESS ARTICLE


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Developmental Biology
Wnt signaling regulates pancreatic {beta} cell proliferation

( Cyclin D2 | diabetes mellitus | islets of Langerhans | pancreas | Pitx2 )

Ingrid C. Rulifson *, Satyajit K. Karnik *, Patrick W. Heiser {dagger}, Derk ten Berge *{ddagger}, Hainan Chen *, Xueying Gu *, Makoto M. Taketo {sect}, Roel Nusse *{ddagger}, Matthias Hebrok {dagger}, and Seung K. Kim *¶||

Departments of *Developmental Biology and Medicine, Oncology Division, Stanford University, Stanford, CA 94305-5329; {dagger}Diabetes Center, University of California, San Francisco, CA 94143-0573; {ddagger}Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-5329; and {sect}Department of Pharmacology, Kyoto University Graduate School of Medicine, Yoshida-Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan

Communicated by Hugh O. McDevitt, Stanford University School of Medicine, Stanford, CA, February 17, 2007 (received for review September 5, 2006)

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 {beta} cell proliferation. The addition of purified Wnt3a protein to cultured {beta} cells or islets promoted expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of {beta} cell cycle progression, and led to increased {beta} cell proliferation in vitro. Conditional pancreatic {beta} cell expression of activated {beta}-catenin, a crucial Wnt signal transduction protein, produced similar phenotypes in vivo, leading to {beta} cell expansion, increased insulin production and serum levels, and enhanced glucose handling. Conditional {beta} cell expression of Axin, a potent negative regulator of Wnt signaling, led to reduced Pitx2 and Cyclin D2 expression by {beta} cells, resulting in reduced neonatal {beta} cell expansion and mass and impaired glucose tolerance. Thus, Wnt signaling is both necessary and sufficient for islet {beta} cell proliferation, and our study provides previously unrecognized evidence of a mechanism governing endocrine pancreas growth and function.

Author contributions: I.C.R., S. K. Karnik, and P.W.H. contributed equally to this work; I.C.R., S. K. Karnik, P.W.H., D.t.B., H.C., R.N., M.H., and S. K. Kim designed research; I.C.R., S. K. Karnik, P.W.H., H.C., and X.G. performed research; D.t.B., M.M.T., and R.N. contributed new reagents/analytic tools; I.C.R., S. K. Karnik, P.W.H., H.C., M.H., and S. K. Kim analyzed data; and I.C.R., S. K. Karnik, P.W.H., and S. K. Kim wrote the paper.

The authors declare no conflict of interest.

Freely available online through the PNAS open access option.

||To whom correspondence should be addressed at: B300 Beckman Center for Molecular and Genetic Medicine, 279 Campus Drive, Stanford, CA 94305-5329.

Seung K. Kim, E-mail: seungkim{at}stanford.edu

www.pnas.org/cgi/doi/10.1073/pnas.0701509104
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