title: GATA4 and GATA6 control mouse pancreas organogenesis.
abstract: Recently, heterozygous mutations in GATA6 have been found in neonatal diabetic patients with failed pancreatic organogenesis. To investigate the roles of GATA4 and GATA6 in mouse pancreas organogenesis, we conditionally inactivated these genes within the pancreas. Single inactivation of either gene did not have a major impact on pancreas formation, indicating functional redundancy. However, double Gata4/Gata6 mutant mice failed to develop pancreata, died shortly after birth, and displayed hyperglycemia. Morphological defects in Gata4/Gata6 mutant pancreata were apparent during embryonic development, and the epithelium failed to expand as a result of defects in cell proliferation and differentiation. The number of multipotent pancreatic progenitors, including PDX1+ cells, was reduced in the Gata4/Gata6 mutant pancreatic epithelium. Remarkably, deletion of only 1 Gata6 allele on a Gata4 conditional knockout background severely reduced pancreatic mass. In contrast, a single WT allele of Gata4 in Gata6 conditional knockout mice was sufficient for normal pancreatic development, indicating differential contributions of GATA factors to pancreas formation. Our results place GATA factors at the top of the transcriptional network hierarchy controlling pancreas organogenesis.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Carrasco
authors.forename: Irene
authors.initials: I
authors.lastname: Delgado
authors.forename: Bernat
authors.initials: B
authors.lastname: Soria
authors.forename: Francisco
authors.initials: F
authors.lastname: Martín
authors.forename: Anabel
authors.initials: A
authors.lastname: Rojas
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D002455:Cell Division; D004847:Epithelial Cells / Q000473:pathology; D050991:GATA4 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050993:GATA6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005838:Genotype; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006943:Hyperglycemia / Q000151:congenital / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D038081:Organogenesis / Q000235:genetics*; D010179:Pancreas / Q000002:abnormalities / Q000196:embryology* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C484171:Gata4 protein, mouse; C494760:Gata6 protein, mouse; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein