Journal
EMBO JOURNAL
Volume 30, Issue 5, Pages 835-845Publisher
WILEY
DOI: 10.1038/emboj.2010.361
Keywords
diabetes; Dicer1; insulin; miRNA; post-transcriptional
Categories
Funding
- Juvenile Diabetes Research Foundation [99-2007-71]
- EFSD/D-Cure Young Investigator award
- Israel Science Foundation
- Yeda-Sela Center for Basic Research
- Wolfson Family Charitable Trust
- Israeli Immigration department
- JDRF
- Helmsley foundation
- EU [241883]
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MicroRNAs (miRNAs) were shown to be important for pancreas development, yet their roles in differentiated beta-cells remain unclear. Here, we show that miRNA inactivation in beta-cells of adult mice results in a striking diabetic phenotype. While islet architecture is intact and differentiation markers are maintained, Dicer1-deficient beta-cells show a dramatic decrease in insulin content and insulin mRNA. As a consequence of the change in insulin content, the animals become diabetic. We provide evidence for involvement of a set of miRNAs in regulating insulin synthesis. The specific knockdown of miR-24, miR-26, miR-182 or miR-148 in cultured beta-cells or in isolated primary islets downregulates insulin promoter activity and insulin mRNA levels. Further, miRNA-dependent regulation of insulin expression is associated with upregulation of transcriptional repressors, including Bhlhe22 and Sox6. Thus, miRNAs in the adult pancreas act in a new network that reinforces insulin expression by reducing the expression of insulin transcriptional repressors. The EMBO Journal (2011) 30, 835-845. doi: 10.1038/emboj.2010.361; Published online 1 February 2011
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