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PNAS 104 (15): 6247-6252

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / DEVELOPMENTAL BIOLOGY

Wnt signaling regulates pancreatic beta cell proliferation

Ingrid C. Rulifson*, Satyajit K. Karnik*, Patrick W. Heiser{dagger}, Derk ten Berge*,{ddagger}, Hainan Chen*, Xueying Gu*, Makoto M. Taketo§, 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 §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 publication September 5, 2006.

Abstract: 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.

Key Words: Cyclin D2 • diabetes mellitus • islets of Langerhans • pancreas • Pitx2


Freely available online through the PNAS open access option.

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.

This article contains supporting information online at www.pnas.org/cgi/content/full/0701509104/DC1.

||To whom correspondence should be addressed at: B300 Beckman Center for Molecular and Genetic Medicine, 279 Campus Drive, Stanford, CA 94305-5329. E-mail: seungkim{at}stanford.edu

© 2007 by The National Academy of Sciences of the USA


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