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Am J Physiol Endocrinol Metab 291: E1305-E1316, 2006. First published May 30, 2006; doi:10.1152/ajpendo.00561.2005
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Islet hypertrophy following pancreatic disruption of Smad4 signaling

Diane M. Simeone,1,2 Lizhi Zhang,1 Mary K. Treutelaar,3 Lanjing Zhang,3 Kathleen Graziano,1 Craig D. Logsdon,2 and Charles F. Burant2,3

Departments of 1Surgery, 2Molecular and Integrative Physiology, and 3Internal Medicine, University of Michigan, Ann Arbor, Michigan

Submitted 16 November 2005 ; accepted in final form 13 April 2006

To investigate the role of transforming growth factor (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. Although E-dnSmad4 mice have normal growth, pancreas weight, and pancreatic exocrine and ductal histology, beginning at 4–6 wk 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.

islet growth; diabetes; nestin; transgenic mice; elastase; transforming growth factor-beta


Address for reprint requests and other correspondence: C. Burant, Univ. of Michigan Medical Center, Box 0678, 1500 E. Medical Center Dr., Ann Arbor, MI 48109 (e-mail: burantc{at}umich.edu)




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