Gata4 is critical to maintain gut barrier function and mucosal integrity following epithelial injury.
The intestinal epithelial barrier is critical to limit potential harmful consequences from exposure to deleterious luminal contents on the organism. Although this barrier is functionally important along the entire gut, specific regional regulatory mechanisms involved in the maintenance of this barrier are poorly defined. Herein, we identified Gata4 as a crucial regulator of barrier integrity in the mouse proximal intestinal epithelium. Conditional deletion of Gata4 in the intestine led to a drastic increase in claudin-2 expression that was associated with an important increase of gut barrier permeability without causing overt spontaneous inflammation. Administration of indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that causes enteritis, led to rapid and restricted proximal small intestinal injuries in Gata4 mutant mice as opposed to control mice. Comparative analysis of gene transcript profiles from indomethacin-challenged control and Gata4 mutant mice identified defects in epithelial cell survival, inflammatory cell recruitment and tissue repair mechanisms. Altogether, these observations identify Gata4 as a novel crucial regulator of the intestinal epithelial barrier and as a critical epithelial transcription factor implicated in the maintenance of proximal intestinal mucosal integrity after injury.
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
David
D
Lepage
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Élise
É
Bélanger
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Christine
C
Jones
Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Sarah
S
Tremblay
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Joannie M
JM
Allaire
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Joannie
J
Bruneau
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Claude
C
Asselin
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Nathalie
N
Perreault
Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Alfredo
A
Menendez
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Fernand-Pierre
FP
Gendron
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Quebec, Canada.
Francois
F
Boudreau
D000818:Animals; D057167:Claudins / Q000378:metabolism; D004751:Enteritis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D007213:Indomethacin / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D012485:Salmonella typhi
D057167:Claudins; C113371:Cldn2 protein, mouse; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D007213:Indomethacin