Islet hypertrophy following pancreatic disruption of Smad4 signaling.
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.
Simeone
Diane M
DM
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Zhang
Lizhi
L
Treutelaar
Mary K
MK
Zhang
Lanjing
L
Graziano
Kathleen
K
Logsdon
Craig D
CD
Burant
Charles F
CF
D000818:Animals; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D005951:Glucose Tolerance Test; D006984:Hypertrophy; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010179:Pancreas / Q000502:physiology*; D010183:Pancreatic Ducts / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051901:Smad4 Protein / Q000235:genetics*; D013936:Thymidine / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
D000963:Antimetabolites; D007328:Insulin; D012333:RNA, Messenger; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D001616:beta-Galactosidase; D010196:Pancreatic Elastase; D001973:Bromodeoxyuridine; D013936:Thymidine