Mir-132 controls beta cell proliferation and survival in mouse model through the PTEN/AKT/FOXO3 signaling

Aim and hypothesis: microRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. However, their diversity as well as the complexity of identifying their endogenous targets and how they are regulated made deciphering their precise role a real challenge. This project was aimed toward the identification of miRNAs and their downstream targets specifically involved in islets beta cells regeneration in mouse model. Methods: Using a partially pancreatectomized mouse model to induce beta cell proliferation, we identified several miRNAs that were differentially expressed in relationship to beta cell replication. The further validated by RT-PCR. Transcriptomic analysis and bioinformatic data mining was then performed to identify the downstream target of miR-132 in insulinoma cell line MIN6 cells, which were then further validated at transcriptional and translational levels. Beta cell proliferation was further assessed in pancreatectomized control and miR-132-/- mice to validate the role of miR-132 in vivo. Results: Sequence specific inhibition of miR-132 correlated with reduced cell proliferation as well as increased apoptosis, whereas its overexpression resulted in reduced apoptosis. Increased levels of miR-132 correlated with repression of PTEN and thus increased Akt signaling and downstream activation of the transcription factor FOXO3a. Consistent with these findings we found that proliferation of beta cell in miR-132-/- pancreatectomized mice was significantly reduced compared to wild-type littermates. Conclusions/Interpretations: Here we have uncovered an exhaustive list of targets and the signaling pathways by which miR-132 controls beta cell proliferation and survival in pancreatic beta cells. The fact that miR-132 controls beta cell proliferation and survival by regulating PTEN activity, the node of Akt/FOXO3 signaling pathway may represent a suitable target to enhance beta cell mass.