title: GATA4 and GATA6 regulate pancreatic endoderm identity through inhibition of hedgehog signaling.
abstract: GATA4 and GATA6 are zinc finger transcription factors that have important functions in several mesodermal and endodermal organs, including heart, liver and pancreas. In humans, heterozygous mutations of either factor are associated with pancreatic agenesis; however, homozygous deletion of both Gata4 and Gata6 is necessary to disrupt pancreas development in mice. In this study, we demonstrate that arrested pancreatic development in Gata4(fl/fl); Gata6(fl/fl); Pdx1:Cre (pDKO) embryos is accompanied by the transition of ventral and dorsal pancreatic fates into intestinal or stomach lineages, respectively. These results indicate that GATA4 and GATA6 play essential roles in maintaining pancreas identity by regulating foregut endodermal fates. Remarkably, pancreatic anlagen derived from pDKO embryos also display a dramatic upregulation of hedgehog pathway components, which are normally absent from the presumptive pancreatic endoderm. Consistent with the erroneous activation of hedgehog signaling, we demonstrate that GATA4 and GATA6 are able to repress transcription through the sonic hedgehog (Shh) endoderm-specific enhancer MACS1 and that GATA-binding sites within this enhancer are necessary for this repressive activity. These studies establish the importance of GATA4/6-mediated inhibition of hedgehog signaling as a major mechanism regulating pancreatic endoderm specification during patterning of the gut tube.
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
authors.forename: Shouhong
authors.initials: S
authors.lastname: Xuan
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032, USA lgs2@cumc.columbia.edu.
authors.forename: Lori
authors.initials: L
authors.lastname: Sussel
mesh_terms: D000818:Animals; D001483:Base Sequence; D019521:Body Patterning; D019070:Cell Lineage; D047369:Chromatin Immunoprecipitation; D003066:Coenzyme A Ligases / Q000502:physiology; D004707:Endoderm / Q000502:physiology*; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000502:physiology*; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000502:physiology; D009154:Mutation; D010179:Pancreas / Q000196:embryology*; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015398:Signal Transduction
chemical_list: D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C484171:Gata4 protein, mouse; C494760:Gata6 protein, mouse; D053823:Hedgehog Proteins; D024101:Mitochondrial Proteins; C499057:Acsm1 protein, mouse; D003066:Coenzyme A Ligases
keywords: Foregut endoderm; GATA4; GATA6; Hedgehog; Mouse; Pancreas