Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

PNAS 104 (15): 6247-6252

Copyright © 2007 by the National Academy of Sciences.


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

||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}

© 2007 by The National Academy of Sciences of the USA

Human {beta}-Cell Proliferation and Intracellular Signaling Part 2: Still Driving in the Dark Without a Road Map.
E. Bernal-Mizrachi, R. N. Kulkarni, D. K. Scott, F. Mauvais-Jarvis, A. F. Stewart, and A. Garcia-Ocana (2014)
Diabetes 63, 819-831
   Abstract »    Full Text »    PDF »
GSK-3{beta} Protein Phosphorylates and Stabilizes HLXB9 Protein in Insulinoma Cells to Form a Targetable Mechanism of Controlling Insulinoma Cell Proliferation.
S. S. Desai, S. D. Modali, V. I. Parekh, E. Kebebew, and S. K. Agarwal (2014)
J. Biol. Chem. 289, 5386-5398
   Abstract »    Full Text »    PDF »
Ku70 Functions in Addition to Nonhomologous End Joining in Pancreatic {beta}-Cells: A Connection to {beta}-Catenin Regulation.
O. Tavana, N. Puebla-Osorio, J. Kim, M. Sang, S. Jang, and C. Zhu (2013)
Diabetes 62, 2429-2438
   Abstract »    Full Text »    PDF »
The Wnt Signaling Pathway Effector TCF7L2 Controls Gut and Brain Proglucagon Gene Expression and Glucose Homeostasis.
W. Shao, D. Wang, Y.-T. Chiang, W. Ip, L. Zhu, F. Xu, J. Columbus, D. D. Belsham, D. M. Irwin, H. Zhang, et al. (2013)
Diabetes 62, 789-800
   Abstract »    Full Text »    PDF »
Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism.
X. Li, J. Shan, W. Chang, I. Kim, J. Bao, H.-J. Lee, X. Zhang, V. T. Samuel, G. I. Shulman, D. Liu, et al. (2012)
PNAS 109, 11402-11407
   Abstract »    Full Text »    PDF »
{beta}-catenin is selectively required for the expansion and regeneration of mature pancreatic acinar cells in mice.
M. D. Keefe, H. Wang, J.-P. De La O, A. Khan, M. A. Firpo, and L. C. Murtaugh (2012)
Dis. Model. Mech. 5, 503-514
   Abstract »    Full Text »    PDF »
Exendin-4 upregulates the expression of Wnt-4, a novel regulator of pancreatic {beta}-cell proliferation.
C. Heller, M. C. Kuhn, B. Mulders-Opgenoorth, M. Schott, H. S. Willenberg, W. A. Scherbaum, and S. Schinner (2011)
Am J Physiol Endocrinol Metab 301, E864-E872
   Abstract »    Full Text »    PDF »
Elevated Hedgehog/Gli signaling causes {beta}-cell dedifferentiation in mice.
L. Landsman, A. Parent, and M. Hebrok (2011)
PNAS 108, 17010-17015
   Abstract »    Full Text »    PDF »
Lmx1a and Lmx1b Function Cooperatively to Regulate Proliferation, Specification, and Differentiation of Midbrain Dopaminergic Progenitors.
C. H. Yan, M. Levesque, S. Claxton, R. L. Johnson, and S.-L. Ang (2011)
J. Neurosci. 31, 12413-12425
   Abstract »    Full Text »    PDF »
TCF7L2 splice variants have distinct effects on {beta}-cell turnover and function.
O. Le Bacquer, L. Shu, M. Marchand, B. Neve, F. Paroni, J. Kerr Conte, F. Pattou, P. Froguel, and K. Maedler (2011)
Hum. Mol. Genet. 20, 1906-1915
   Abstract »    Full Text »    PDF »
Global gene expression profiling in early-stage polycystic kidney disease in the Han:SPRD Cy rat identifies a role for RXR signaling.
M. Kugita, K. Nishii, M. Morita, D. Yoshihara, H. Kowa-Sugiyama, K. Yamada, T. Yamaguchi, D. P. Wallace, J. P. Calvet, H. Kurahashi, et al. (2011)
Am J Physiol Renal Physiol 300, F177-F188
   Abstract »    Full Text »    PDF »
Insulin treatment and high-fat diet feeding reduces the expression of three Tcf genes in rodent pancreas.
J. Columbus, Y. Chiang, W. Shao, N. Zhang, D. Wang, H. Y. Gaisano, Q. Wang, D. M. Irwin, and T. Jin (2010)
J. Endocrinol. 207, 77-86
   Abstract »    Full Text »    PDF »
Effects of Regulator of G Protein Signaling 19 (RGS19) on Heart Development and Function.
Y. R. Ji, M. O. Kim, S. H. Kim, D. H. Yu, M. J. Shin, H. J. Kim, H. S. Yuh, K. B. Bae, J. Y. Kim, H. D. Park, et al. (2010)
J. Biol. Chem. 285, 28627-28634
   Abstract »    Full Text »    PDF »
Increased {beta}-Cell Mass by Islet Transplantation and PLAG1 Overexpression Causes Hyperinsulinemic Normoglycemia and Hepatic Insulin Resistance in Mice.
J. Declercq, A. Kumar, J. A. Van Diepen, I. O. C. M. Vroegrijk, C. Gysemans, C. Di Pietro, P. J. Voshol, C. Mathieu, N. Ectors, W. J. M. Van de Ven, et al. (2010)
Diabetes 59, 1957-1965
   Abstract »    Full Text »    PDF »
R-spondin-1 Is a Novel {beta}-Cell Growth Factor and Insulin Secretagogue.
V. S. C. Wong, A. Yeung, W. Schultz, and P. L. Brubaker (2010)
J. Biol. Chem. 285, 21292-21302
   Abstract »    Full Text »    PDF »
Neonatal growth and regeneration of {beta}-cells are regulated by the Wnt/{beta}-catenin signaling in normal and diabetic rats.
F. Figeac, B. Uzan, M. Faro, N. Chelali, B. Portha, and J. Movassat (2010)
Am J Physiol Endocrinol Metab 298, E245-E256
   Abstract »    Full Text »    PDF »
Nuclear-Cytoplasmic Shuttling of Menin Regulates Nuclear Translocation of {beta}-Catenin.
Y. Cao, R. Liu, X. Jiang, J. Lu, J. Jiang, C. Zhang, X. Li, and G. Ning (2009)
Mol. Cell. Biol. 29, 5477-5487
   Abstract »    Full Text »    PDF »
Conditional Mutations of {beta}-Catenin and APC Reveal Roles for Canonical Wnt Signaling in Lens Differentiation.
G. Martinez, M. Wijesinghe, K. Turner, H. E. Abud, M. M. Taketo, T. Noda, M. L. Robinson, and R. U. de Iongh (2009)
Invest. Ophthalmol. Vis. Sci. 50, 4794-4806
   Abstract »    Full Text »    PDF »
Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function.
L. Shu, A. V. Matveyenko, J. Kerr-Conte, J.-H. Cho, C. H.S. McIntosh, and K. Maedler (2009)
Hum. Mol. Genet. 18, 2388-2399
   Abstract »    Full Text »    PDF »
Conditional Deletion of Beta-Catenin Mediated by Amhr2cre in Mice Causes Female Infertility.
J. A. Hernandez Gifford, M. E. Hunzicker-Dunn, and J. H. Nilson (2009)
Biol Reprod 80, 1282-1292
   Abstract »    Full Text »    PDF »
Pathophysiological aspects of Wnt-signaling in endocrine disease.
S. Schinner, H. S Willenberg, M. Schott, and W. A Scherbaum (2009)
Eur. J. Endocrinol. 160, 731-737
   Abstract »    Full Text »    PDF »
Polycomb protein Ezh2 regulates pancreatic {beta}-cell Ink4a/Arf expression and regeneration in diabetes mellitus.
H. Chen, X. Gu, I-h. Su, R. Bottino, J. L. Contreras, A. Tarakhovsky, and S. K. Kim (2009)
Genes & Dev. 23, 975-985
   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase-3 and Mammalian Target of Rapamycin Pathways Contribute to DNA Synthesis, Cell Cycle Progression, and Proliferation in Human Islets.
H. Liu, M. S. Remedi, K. L. Pappan, G. Kwon, N. Rohatgi, C. A. Marshall, and M. L. McDaniel (2009)
Diabetes 58, 663-672
   Abstract »    Full Text »    PDF »
Identification of small-molecule inducers of pancreatic {beta}-cell expansion.
W. Wang, J. R. Walker, X. Wang, M. S. Tremblay, J. W. Lee, X. Wu, and P. G. Schultz (2009)
PNAS 106, 1427-1432
   Abstract »    Full Text »    PDF »
Menin Promotes the Wnt Signaling Pathway in Pancreatic Endocrine Cells.
G. Chen, J. A, M. Wang, S. Farley, L.-Y. Lee, L.-C. Lee, and M. P. Sawicki (2008)
Mol. Cancer Res. 6, 1894-1907
   Abstract »    Full Text »    PDF »
Conditional inactivation of Myc impairs development of the exocrine pancreas.
H. Nakhai, J. T. Siveke, L. Mendoza-Torres, and R. M. Schmid (2008)
Development 135, 3191-3196
   Abstract »    Full Text »    PDF »
Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of {beta}-catenin in mice.
T. Grigoryan, P. Wend, A. Klaus, and W. Birchmeier (2008)
Genes & Dev. 22, 2308-2341
   Abstract »    Full Text »    PDF »
On the origin of the {beta} cell.
J. M. Oliver-Krasinski and D. A. Stoffers (2008)
Genes & Dev. 22, 1998-2021
   Abstract »    Full Text »    PDF »
Targeted disruption of {beta}-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex.
A. C. Kim, A. L. Reuter, M. Zubair, T. Else, K. Serecky, N. C. Bingham, G. G. Lavery, K. L. Parker, and G. D. Hammer (2008)
Development 135, 2593-2602
   Abstract »    Full Text »    PDF »
The protein tyrosine phosphatase-BL, modulates pancreatic {beta}-cell proliferation by interaction with the Wnt signalling pathway.
H. J Welters, A. Oknianska, K. S Erdmann, G. U Ryffel, and N. G Morgan (2008)
J. Endocrinol. 197, 543-552
   Abstract »    Full Text »    PDF »
Glucagon-like Peptide-1 Activation of TCF7L2-dependent Wnt Signaling Enhances Pancreatic Beta Cell Proliferation.
Z. Liu and J. F. Habener (2008)
J. Biol. Chem. 283, 8723-8735
   Abstract »    Full Text »    PDF »
{beta}-Cell Replication by Loosening the Brakes of Glucagon-Like Peptide-1 Receptor Signaling.
F. C. Schuit and D. J. Drucker (2008)
Diabetes 57, 529-531
   Full Text »    PDF »
ICA512 signaling enhances pancreatic -cell proliferation by regulating cyclins D through STATs.
H. Mziaut, S. Kersting, K.-P. Knoch, W.-H. Fan, M. Trajkovski, K. Erdmann, H. Bergert, F. Ehehalt, H.-D. Saeger, and M. Solimena (2008)
PNAS 105, 674-679
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882