Cx36 Is a Target of Beta2/NeuroD1, Which Associates with Prenatal Differentiation of Insulin-producing β Cells
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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.
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