MiRNAs control insulin content in pancreatic β 2-cells via downregulation of transcriptional repressors

Tal Melkman-Zehavi, Roni Oren, Sharon Kredo-Russo, Tirosh Shapira, Amitai D. Mandelbaum, Natalia Rivkin, Tomer Nir, Kim A. Lennox, Mark A. Behlke, Yuval Dor, Eran Hornstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

247 Scopus citations

Abstract

MicroRNAs (miRNAs) were shown to be important for pancreas development, yet their roles in differentiated β 2-cells remain unclear. Here, we show that miRNA inactivation in β 2-cells of adult mice results in a striking diabetic phenotype. While islet architecture is intact and differentiation markers are maintained, Dicer1-deficient β 2-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 β 2-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.

Original languageAmerican English
Pages (from-to)835-845
Number of pages11
JournalEMBO Journal
Volume30
Issue number5
DOIs
StatePublished - 2 Mar 2011

Keywords

  • Dicer1
  • diabetes
  • insulin
  • miRNA
  • post-transcriptional

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