FIGURE 2.

Regulation of β-cell identity by miR-7 (A) miR-7 gene circuits prevailing in pancreatic β-cells. Functional analyses revealed that miR-7 controls three essential axes maintaining the identity of pancreatic β-cells: (1) Insulin gene transcription (left); (2) Insulin secretion (middle); and (3) β-cell proliferation (right). miR-7 represses Pax6 and Gata6 mRNAs, two transcription factors modulating insulin gene transcription. miR-7 also controls the expression of PKCβ, a Ser/Thr protein kinase activated following Ca²⁺ release, and SNCα and CSPα, two components of the exocytosis machinery modulating SNARE activity and the late step of insulin granule fusion with the plasma membrane. Finally, evidence indicate that miR-7 is a negative regulator of β-cell proliferation by repressing the expression of core components of the mTOR signaling pathways including p70S6K, eIF4e, Mapkap1, and Mknk1/2. By concomitantly repressing targets of these three axes, miR-7 couples rates in insulin transcription and secretion to β-cell proliferation. ^∗Denotes a direct target of miR-7. (B) Regulation of miR-7 expression mediates the functional adaptation of β-cells to metabolic stress. Schematic illustrating the progressive changes in glucose (blue) and insulin (green) concentrations as well as in islet miR-7 expression (red) during the physio-pathological progression of type 2 diabetes. Fluctuations of these parameters are supported from data obtained with miR-7 mutants mice, mouse models of obesity and diabetes, as well as observations made in primary human islets and obese and diabetic patients. Data source: Esguerra et al. (2011), Kredo-Russo et al. (2012), Wang et al. (2013a), Latreille et al. (2014). See the main text for further details.