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Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice
  1. Paola Martinelli1,
  2. Marta Cañamero2,
  3. Natalia del Pozo1,
  4. Francesc Madriles1,
  5. Agustín Zapata3,
  6. Francisco X Real1,4
  1. 1Epithelial Carcinogenesis Group, Molecular Pathology Programme, CNIO-Spanish National Cancer Research Centre, Madrid, Spain
  2. 2Comparative Pathology Unit, Biotechnology Programme, CNIO, Madrid, Spain
  3. 3Department of Cell Biology, Universidad Complutense, Madrid, Spain
  4. 4Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
  1. Correspondence to Dr Francisco X Real, Programa de Patología Molecular, CNIO-Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid 28029, Spain; freal{at}cnio.es

Abstract

Objectives 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.

Design 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.

  • Exocrine Pancreatic Function
  • Differentiation
  • Ageing
  • Cell Biology
  • Pancreatic Damage

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