miR-7a is regulated in beta-cell dysfunction and couples early and late stages of pancreatic beta-cell differentiation to insulin secretion

Transcriptional and posttranscriptional regulatory networks play a crucial role in the maintenance and adaptation of pancreatic beta-cell function. In this study we show that the levels of the prototypic neuroendocrine miRNA-7 are regulated in islets of obese, diabetic and aged mouse models. Using gain- and loss-of-function models we demonstrate that miR-7 regulates crucial members of the endocrine pancreatic transcriptional network controlling differentiation and insulin synthesis. Importantly, it also directly regulates key proteins in the insulin granule secretory machinery. These results reveal an interconnecting miR-7 genomic circuit that influences beta-cell differentiation, insulin synthesis and release and define a role for miR-7 as an endocrine checkpoint to stabilize beta-cell function during metabolic stress. These findings have implications for miR-7 inhibitors as potential therapies for type 2 diabetes and neurodegenerative diseases. Either miR-7a2 or miR-7b were over-expressed in MIN6 cells using an adenoviral vector. The miR-7a infection was performed in duplicates. In addition, a GFP over-expression in MIN6 using the same viral vector served as control. We also explored the consequence of miR-7a2 deletion in pancreatic beta-cells by generating a beta-cells specific miR-7a2 knock-out using the Lox/Cre system in a C57BL/6 background. We profiled gene expression in mutant and wild-type (control) islets.