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J. Biol. Chem., Vol. 282, Issue 27, 19575-19588, July 6, 2007

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MicroRNA-124a Regulates Foxa2 Expression and Intracellular Signaling in Pancreatic β-Cell Lines^*

Nadine Baroukh¹, Magalie A. Ravier, Merewyn K. Loder, Elaine V. Hill, Ali Bounacer^¶, Raphaël Scharfmann^¶, Guy A. Rutter, and Emmanuel Van Obberghen²

From the INSERM, U145, Nice, F-06107 France and Université de Nice-Sophia Antipolis, FacultédeMédecine, Institut de Génétique et Signalisation Moléculaire (IFR50), Nice, F-06107 France, the Department of Cell Biology, Division of Medicine, Faculty of Medicine, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom, and the ^¶INSERM EMI 0363, Paris F-75015 France and Site Necker, FacultédeMédecine René Descartes, Université Paris-Descartes, Paris, France

MicroRNAs (miRNAs) are short non-coding RNAs that have been implicated in fine-tuning gene regulation, although the precise roles of many are still unknown. Pancreatic development is characterized by the complex sequential expression of a gamut of transcription factors. We have performed miRNA expression profiling at two key stages of mouse embryonic pancreas development, e14.5 and e18.5. miR-124a2 expression was strikingly increased at e18.5 compared with e14.5, suggesting a possible role in differentiated β-cells. Among the potential miR-124a gene targets identified by biocomputation, Foxa2 is known to play a role in β-cell differentiation. To evaluate the impact of miR-124a2 on gene expression, we overexpressed or down-regulated miR-124a2 in MIN6 β-cells. As predicted, miR-124a2 regulated Foxa2 gene expression, and that of its downstream target, pancreatic duodenum homeobox-1 (Pdx-1). Foxa2 has been described as a master regulator of pancreatic development and also of genes involved in glucose metabolism and insulin secretion, including the ATP-sensitive K⁺ (K_ATP) channel subunits, Kir6.2 and Sur-1. Correspondingly, miR-124a2 overexpression decreased, and anti-miR-124a2 increased Kir6.2 and Sur-1 mRNA levels. Moreover, miR-124a2 modified basal and glucose- or KCl-stimulated intracellular free Ca²⁺ concentrations in single MIN6 and INS-1 (832/13) β-cells, without affecting the secretion of insulin or co-transfected human growth hormone, consistent with an altered sensitivity of the β-cell exocytotic machinery to Ca²⁺. In conclusion, whereas the precise role of microRNA-124a2 in pancreatic development remains to be deciphered, we identify it as a regulator of a key transcriptional protein network in β-cells responsible for modulating intracellular signaling.

Received for publication, December 27, 2006 , and in revised form, March 22, 2007.

^* This work was supported at INSERM 145 (Nice) by INSERM-Fondation pour La Recherche Médicale-Juvenile Diabetes Research Foundation International (FRM-JDRF) Grant 4DA03H and the European Foundation for the Study of Diabetes (EFSD)/JDRF/Novo-Nordisk Program in Type 1 Diabetes (to E. V. O.). Research performed by the Department of Cell Biology (London) was supported by Juvenile Diabetes Research Foundation International Grant 1-2003-235, Wellcome Trust Programme Grant 067081/Z/02/Z, and a Research Leave Fellowship (to G. A. R.), Medical Research Council Grant G0401641 and Medical Research Council Infrastructure grant to the University of Bristol (UK) MRC Imaging Facility. Additional support to INSERM 145 (Nice) was provided by INSERM, Conseil Régional PACA and Conseil Général des Alpes-Maritimes, Université de Nice-Sophia Antipolis, and by European Community FP6 EUGENE 2 Grant LSHM-CT-2004-512013. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and Figs. S1–S3.

¹ Supported by grants from INSERM-FRM-JDRF and EFSD/JDRF/Novo-Nordisk Program in Type 1 Diabetes.

² To whom correspondence should be addressed. Tel.: 33-4-93-81-54-47; Fax: 33-4-93-81-54-32; E-mail: vanobbeg{at}unice.fr.

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