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Am J Physiol Endocrinol Metab (May 30, 2006). doi:10.1152/ajpendo.00561.2005
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Submitted on November 16, 2005
Accepted on April 13, 2006

Islet Hypertrophy Following Pancreatic Disruption of Smad4 Signaling

Diane M. Simeone1, Lizhi Zhang2, Mary K. Treutelaar3, Lanjing Zhang3, Kathleen Graziano2, Craig D Logsdon4, and Charles F. Burant5*

1 Surgery, University of Michigan, Ann Arbor, Michigan, United States; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
2 Surgery, University of Michigan, Ann Arbor, Michigan, United States
3 Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
4 Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
5 Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States

* To whom correspondence should be addressed. E-mail: burantc{at}umich.edu.

To investigate the role of TGF{beta}-family signaling in the adult pancreas, a transgenic mouse (E-dnSmad4) was created that expresses a dominant-negative Smad4 protein driven by a fragment of the elastase promoter. While E-dnSmad4 mice have normal growth, pancreas weight and pancreatic exocrine and ductal histology, beginning at 4-6 weeks of age, E-dnSmad4 mice show an age-dependent increase in the size of islets. In parallel, an expanded population of replicating cells expressing the E-dnSmad4 transgene is found in the stroma between the enlarged islets and pancreatic ducts. Despite the marked enlargement, E-dnSmad4 islets contain normal ratios and spatial organization of endocrine cell subtypes and have normal glucose homeostasis. Replication of cells derived from primary duct cultures of wild type mice, but not E-dnSmad4 mice, was inhibited by the addition of TGF{beta}-family proteins, demonstrating a cell-autonomous effect of the transgene. These data show that in the adult pancreas, TGF{beta}-family signaling plays a role in islet size by regulating the growth of a pluripotent progenitor cell residing in the periductal stroma of the pancreas.




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[Abstract] [Full Text] [PDF]


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