title: Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice.
abstract: OBJECTIVE
  Previous studies have suggested an important role of the transcription factor Gata6 in endocrine pancreas, while GATA6 haploinsufficient inactivating mutations cause pancreatic agenesis in humans. We aimed to analyse the effects of Gata6 inactivation on pancreas development and function.
  
  
  METHODS
  We deleted Gata6 in all epithelial cells in the murine pancreas at the onset of its development. Acinar proliferation, apoptosis, differentiation and exocrine functions were assessed using reverse transcriptase quantitative PCR (RT-qPCR), chromatin immunoprecipitation, immunohistochemistry and enzyme assays. Adipocyte transdifferentiation was assessed using electron microscopy and genetic lineage tracing.
  
  
  RESULTS
  Gata6 is expressed in all epithelial cells in the adult mouse pancreas but it is only essential for exocrine pancreas homeostasis: while dispensable for pancreatic development after e10.5, it is required for complete acinar differentiation, for establishment of polarity and for the maintenance of acinar cells in the adult. Gata6 regulates directly the promoter of genes coding for digestive enzymes and the transcription factors Rbpjl and Mist1. Upon pancreas-selective Gata6 inactivation, massive loss of acinar cells and fat replacement take place. This is accompanied by increased acinar apoptosis and proliferation, acinar-to-ductal metaplasia and adipocyte transdifferentiation. By contrast, the endocrine pancreas is spared.
  
  
  CONCLUSIONS
  Our data show that Gata6 is required for the complete differentiation of acinar cells through multiple transcriptional regulatory mechanisms. In addition, it is required for the maintenance of the adult acinar cell compartment. Our studies suggest that GATA6 alterations may contribute to diseases of the human adult exocrine pancreas.
authors.affiliation: Epithelial Carcinogenesis Group, Molecular Pathology Programme, CNIO-Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Paola
authors.initials: P
authors.lastname: Martinelli
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Natalia
authors.initials: N
authors.lastname: del Pozo
authors.forename: Francesc
authors.initials: F
authors.lastname: Madriles
authors.forename: Agustín
authors.initials: A
authors.lastname: Zapata
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
mesh_terms: D061354:Acinar Cells / Q000166:cytology* / Q000473:pathology / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D005260:Female; D050993:GATA6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D008297:Male; D008679:Metaplasia / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000254:growth & development / Q000473:pathology / Q000502:physiology
chemical_list: D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse