title: The transcription factor hepatocyte nuclear factor-6/Onecut-1 controls the expression of its paralog Onecut-3 in developing mouse endoderm.
abstract: During development, the endoderm gives rise to several organs, including the pancreas and liver. This differentiation process requires spatial and temporal regulation of gene expression in the endoderm by a network of tissue-specific transcription factors whose elucidation is far from complete. These factors include the Onecut protein hepatocyte nuclear factor-6 (HNF-6), which controls pancreas and liver development as shown in our previous work on Hnf6 knock-out embryos. In mammals, HNF-6 has two paralogs, Onecut-2 (OC-2) and OC-3, whose patterns of expression in the adult overlap with that of HNF-6. In the present work, we examine the expression profile of the three Onecut factors in the developing mouse endoderm. We show that HNF-6, OC-2, and OC-3 are expressed sequentially, which defines new steps in endoderm differentiation. By analyzing Hnf6 knock-out embryos we find that HNF-6 is required for expression of the Oc3 gene in the endoderm. We show that OC-3 colocalizes with HNF-6 in the endoderm and in embryonic pancreas and liver. Based on transfection, chromatin immunoprecipitation, and whole embryo electroporation experiments, we demonstrate that HNF-6 can bind to and stimulate the expression of the Oc3 gene. This study identifies a regulatory cascade between two paralogous transcription factors, sheds new light on the interpretation of the Hnf6 knock-out phenotype, and broadens the transcription factors network operating during development of the endoderm, liver, and pancreas.
authors.affiliation: Hormone and Metabolic Research Unit, Institute of Cellular Pathology and Université catholique de Louvain, 75 Avenue Hippocrate, B-1200 Brussels, Belgium. pierreux@horm.ucl.ac.be
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Pierreux
authors.forename: Vinciane
authors.initials: V
authors.lastname: Vanhorenbeeck
authors.forename: Patrick
authors.initials: P
authors.lastname: Jacquemin
authors.forename: Frédéric P
authors.initials: FP
authors.lastname: Lemaigre
authors.forename: Guy G
authors.initials: GG
authors.lastname: Rousseau
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018076:DNA, Complementary / Q000378:metabolism; D018274:Electroporation; D004622:Embryo, Mammalian / Q000166:cytology; D004707:Endoderm / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins / Q000502:physiology*; D008099:Liver / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009924:Organ Culture Techniques; D010179:Pancreas / Q000196:embryology; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; C496606:Onecut1 protein, mouse; C454106:Onecut3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D012313:RNA