EXPRESSION OF A DOMINANT-NEGATIVE MUTANT TGF-BETA TYPE-II RECEPTOR INTRANSGENIC MICE REVEALS ESSENTIAL ROLES FOR TGF-BETA IN REGULATION OFGROWTH AND DIFFERENTIATION IN THE EXOCRINE PANCREAS

Using a dominant-negative mutant receptor (DNR) approach in transgenic mice, we have functionally inactivated transforming growth factor-bet a (TGF-beta) signaling in select epithelial cells, The dominant-negati ve mutant type II TGF-beta receptor blocked signaling by all three TGF -beta isoforms in primary hepatocyte and pancreatic acinar cell cultur es generated from transgenic mice, as demonstrated by the loss of grow th inhibitory and gene induction responses, However, it had no effect on signaling by activin, the closest TGF-beta family member, DNR trans genic mice showed increased proliferation of pancreatic acinar cells a nd severely perturbed acinar differentiation. These results indicate t hat TGF-beta negatively controls growth of acinar cells and is essenti al for the maintenance of a differentiated acinar phenotype in the exo crine pancreas in vivo. In contrast, such abnormalities were not obser ved in the liver, Additional abnormalities in the pancreas included fi brosis, neoangiogenesis and mild macrophage infiltration, and these we re associated with a marked up-regulation of TGF-beta expression in tr ansgenic acinar cells, This transgenic model of targeted functional in activation of TGF-beta signaling provides insights into mechanisms whe reby loss of TGF-beta responsiveness might promote the carcinogenic pr ocess, both through direct effects on cell proliferation, and indirect ly through up-regulation of TGF-beta s with associated paracrine effec ts on stromal compartments.