ATF2 and ATF7 are critical mediators of intestinal epithelial repair
2020
Abstract Background and Aims AP-1 transcription factor family members activating transcription factor 2 and 7 (ATF2 and ATF7) have highly redundant functions due to highly homologous DNA-binding sites. Their role in intestinal epithelial homeostasis and repair is unknown. Here, we assess the role of these proteins in these conditions in a intestine specific mouse model. Methods We performed in- and ex vivo experiments utilizing Villin-CreERT2Atf2fl/flAtf7ko/ko mice. We investigated the effects of intestinal epithelium specific deletion of the Atf2 DNA binding region in Atf7-/- mice on cellular proliferation, differentiation, apoptosis, and epithelial barrier function under homeostatic conditions. Subsequently, we exposed mice to 2% Dextran Sulfate Sodium (DSS) for 7 days and 12Gy whole body irradiation and assessed the response to epithelial damage. Results Activating phosphorylation of ATF2 and ATF7 was mainly detected in the crypts of the small intestine and lower crypt region of the colonic epithelium. Under homeostatic conditions, no major phenotypic changes were detectable in the intestine of ATF mutant mice. However, upon DSS exposure or whole body irradiation, the intestinal epithelium showed a clearly impaired regenerative response. Mutant mice developed severe ulceration and inflammation associated with increased epithelial apoptosis upon DSS exposure and were less able to regenerate colonic crypts upon irradiation. In vitro, organoids derived from double mutant epithelium had a growth disadvantage compared to wild type organoids, impaired wound healing capacity in scratch assay and increased sensitivity to TNF-α-induced damage. Conclusion ATF2 and ATF7 are dispensable for epithelial homeostasis, but are required to maintain epithelial regenerative capacity and protect against cell death during intestinal epithelial damage and repair.
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