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A vHNF1/TCF2-HNF6 Cascade Regulates the Transcription Factor Network That Controls Generation of Pancreatic Precursor Cells

¹ Hormone and Metabolic Research Unit, Université Catholique de Louvain and Institute of Cellular Pathology, Brussels, Belgium
² Unité Mixte de Recherche 7622, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, Paris, France
³ Laboratory of Physiological Chemistry, Université Catholique de Louvain and Institute of Cellular Pathology, Brussels, Belgium

Address correspondence and reprint requests to Frédéric Lemaigre, Hormone and Metabolic Research Unit, Université Catholique de Louvain and Institute of Cellular Pathology, Avenue Hippocrate 75/7529, B-1200 Brussels, Belgium. E-mail: lemaigre{at}horm.ucl.ac.be

Abbreviations: C/EBP, CAAT/enhancer-binding protein; EMSA, electrophoretic mobility shift assay; FoxA, forkhead box A; Pdx, pancreatic and duodenal homeobox; Sp, specific protein; Ptf1a, pancreas transcription factor 1a; (v)HNF, (variant) hepatocyte nuclear factor

Generation of pancreatic precursor cells in the endoderm is controlled by a network of transcription factors. Hepatocyte nuclear factor-6 (HNF6) is a key player in this network, because it controls the initiation of the expression of pancreatic and duodenal homeobox 1 (Pdx1), the earliest marker of pancreatic precursor cells. To further characterize this network, we have investigated how the expression of HNF6 is controlled in mouse endoderm, by using in vitro and in vivo protein-DNA interaction techniques combined with endoderm electroporation, transgenesis, and gene inactivation in embryos. We delineated Hnf6 regulatory regions that confer expression of a reporter gene in the embryonic endoderm but not in extraembryonic visceral endoderm. HNF6 expression in the embryonic endoderm was found to depend on an intronic enhancer. This enhancer contains functional binding sites for the tissue-specific factors of the forkhead box A and HNF1 families. Among the latter, variant HNF1 (vHNF1)/TCF2, which is expressed before HNF6 in the endoderm, was found to be critical for HNF6 expression. Therefore, the sequential activation of vHNF1, HNF6, and Pdx1 in the endoderm appears to control the generation of pancreatic precursors. This cascade may be used to benchmark in vitro differentiation of pancreatic precursor cells from embryonic stem cells, for cell therapy of diabetes.

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