SMAD7 enhances adult β-cell proliferation without significantly affecting β-cell function in mice

Abstract

The interplay between the transforming growth factor β (TGF-β) signaling proteins, SMAD family member 2 (SMAD2) and 3 (SMAD3), and the TGF-β-inhibiting SMAD, SMAD7, seems to play a vital role in proper pancreatic endocrine development and also in normal β-cell function in adult pancreatic islets. Here, we generated conditional SMAD7 knockout mice by crossing insulin1Cre mice withSMAD7fx/fx mice.Wealso created a β cell-specific SMAD7-overexpressing mouse line by crossing insulin1Dre mice with HPRT-SMAD7/RosaGFP mice. We analyzed β-cell function in adult islets when SMAD7 was either absent or overexpressed in β cells. Loss of SMAD7 in β cells inhibited proliferation, and SMAD7 overexpression enhanced cell proliferation. However, alterations in basic glucose homeostasis were not detectable following either SMAD7 deletion or overexpression inβ cells. Our results show that both the absence and overexpression of SMAD7 affect TGF-β signaling and modulates β-cell proliferation but does not appear to alter β-cell function. Reversible SMAD7 overexpression may represent an attractive therapeutic option to enhance β-cell proliferation without negative effects on β-cell function.