GATA6 is required for proliferation, migration, secretory cell maturation, and gene expression in the mature mouse colon.
Controlled renewal of the epithelium with precise cell distribution and gene expression patterns is essential for colonic function. GATA6 is expressed in the colonic epithelium, but its function in the colon is currently unknown. To define GATA6 function in the colon, we conditionally deleted Gata6 throughout the epithelium of small and large intestines of adult mice. In the colon, Gata6 deletion resulted in shorter, wider crypts, a decrease in proliferation, and a delayed crypt-to-surface epithelial migration rate. Staining techniques and electron microscopy indicated deficient maturation of goblet cells, and coimmunofluorescence demonstrated alterations in specific hormones produced by the endocrine L cells and serotonin-producing cells. Specific colonocyte genes were significantly downregulated. In LS174T, the colonic adenocarcinoma cell line, Gata6 knockdown resulted in a significant downregulation of a similar subset of goblet cell and colonocyte genes, and GATA6 was found to occupy active loci in enhancers and promoters of some of these genes, suggesting that they are direct targets of GATA6. These data demonstrate that GATA6 is necessary for proliferation, migration, lineage maturation, and gene expression in the mature colonic epithelium.
Division of Gastroenterology and Nutrition, Department of Medicine, Children's Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.
Eva
E
Beuling
Boaz E
BE
Aronson
Luc M D
LM
Tran
Kelly A
KA
Stapleton
Ellis N
EN
ter Horst
Laurens A T M
LA
Vissers
Michael P
MP
Verzi
Stephen D
SD
Krasinski
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003106:Colon / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000166:cytology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice
D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse