Cx36 Is a Target of Beta2/NeuroD1, Which Associates with Prenatal Differentiation of Insulin-producing β Cells
- 302 Downloads
The insulin-producing β cells of pancreatic islets are coupled by connexin36 (Cx36) channels. To investigate what controls the expression of this connexin, we have investigated its pattern during mouse pancreas development, and the influence of three transcription factors that are critical for β-cell development and differentiation. We show that (1) the Cx36 gene (Gjd2) is activated early in pancreas development and is markedly induced at the time of the surge of the transcription factors that determine β-cell differentiation; (2) the cognate protein is detected about a week later and is selectively expressed by β cells throughout the prenatal development of mouse pancreas; (3) a 2-kbp fragment of the Gjd2 promoter, which contains three E boxes for the binding of the bHLH factor Beta2/NeuroD1, ensures the expression of Cx36 by β cells; and (4) Beta2/NeuroD1 binds to these E boxes and, in the presence of the E47 ubiquitous cofactor, transactivates the Gjd2 promoter. The data identify Cx36 as a novel early marker of β cells and as a target of Beta2/NeuroD1, which is essential for β-cell development and differentiation.
KeywordsBeta2/neurod1 Connexin Gap junctions Gene regulation Pancreas Promoter Transcription factor
Our team is supported by Grants from the Swiss National Science Foundation (310000-141162, IZ73Z0_127935, CR32I3_129987), the Juvenile Diabetes Research Foundation (40-2011-11, 5-2012-281), and the European Union (BETAIMAGE 222980; IMIDIA C2008-T7, BETATRAIN 289932). We are pleased to dedicate this study to Ross G. Johnson on occasion of the starting of his new life. Ross has been a pioneer in our field, a passionate and influential scholar, and a much appreciated host while Paolo was striving in snowy Minneapolis. We wish him all the best for a new exciting adventure.
- Carvalho CP, Oliveira RB, Britan A, Silva-Santos JC, Boschero AC, Meda P, Collares-Buzato CB (2012) Impaired beta-to-beta cell coupling mediated by Cx36 gap junctions in pre-diabetic mice. Am J Physiol Endocrinol Metab 302 (in press)Google Scholar
- Head WS, Orseth ML, Nunemaker CS, Satin LS, Piston DW, Benninger RK (2012) Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse. Diabetes 61 (in press)Google Scholar
- Martin D, Tawadros T, Meylan L, Abderrahmani A, Condorelli DF, Waeber G, Haefliger JA (2003) Critical role of the transcriptional repressor neuron-restrictive silencer factor in the specific control of connexin36 in insulin-producing cell lines. J Biol Chem 278:53082–53089PubMedCrossRefGoogle Scholar
- Meda P (2012) The in vivo β-to-β-cell chat room: connexin connections matter. Diabetes 61 (in press)Google Scholar
- Pérez-Armendariz EM, Cruz-Miguel L, Coronel-Cruz C, Esparza-Aguilar M, Pinzon-Estrada E, Rancaño-Camacho E, Zacarias-Climaco G, Olivares PF, Espinosa AM, Becker I, Sáez JC, Berumen J, Pérez-Palacios G (2012) Connexin 36 is expressed in beta and connexins 26 and 32 in acinar cells at the end of the secondary transition of mouse pancreatic development and increase during fetal and perinatal life. Anat Rec 295:980–990CrossRefGoogle Scholar
- Potolicchio I, Cigliola V, Velazquez-Garcia S, Klee P, Valjevac A, Kapic D, Cosovic E, Lepara O, Hadzovic-Dzuvo A, Mornjacovic Z, Meda P (2012) Connexin-dependent signaling in neuro-hormonal systems. Biochim Biophys Acta 1818:1919–1936Google Scholar
- Ravier MA, Guldenagel M, Charollais A, Gjinovci A, Caille D, Sohl G, Wollheim CB, Willecke K, Henquin JC, Meda P (2005) Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release. Diabetes 54:1798–1807PubMedCrossRefGoogle Scholar
- Serre-Beinier V, Bosco D, Zulianello L, Charollais A, Caille D, Charpantier E, Gauthier BR, Diaferia GR, Giepmans BN, Lupi R, Marchetti P, Deng S, Buhler L, Berney T, Cirulli V, Meda P (2009) Cx36 makes channels coupling human pancreatic beta-cells, and correlates with insulin expression. Hum Mol Genet 18:428–439PubMedCrossRefGoogle Scholar
- Theis M, Mas C, Doring B, Degen J, Brink C, Caille D, Charollais A, Kruger O, Plum A, Nepote V, Herrera P, Meda P, Willecke K (2004) Replacement by a lacZ reporter gene assigns mouse connexin36, 45 and 43 to distinct cell types in pancreatic islets. Exp Cell Res 294:18–29PubMedCrossRefGoogle Scholar
- Wellershaus K, Degen J, Deuchars J, Theis M, Charollais A, Caille D, Gauthier B, Janssen-Bienhold U, Sonntag S, Herrera P, Meda P, Willecke K (2008) A new conditional mouse mutant reveals specific expression and functions of connexin36 in neurons and pancreatic beta-cells. Exp Cell Res 314:997–1012PubMedCrossRefGoogle Scholar