GATA6 Is Required for Proliferation, Migration, Secretory Cell Maturation, and Gene Expression in the Mature Mouse Colon

Abstract

e 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.

The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

“…GATA-4, -5 and -6 are found mainly in the heart and endoderm-derived tissues, including the liver, lungs, pancreas, stomach and intestines 18 . Furthermore, it has been reported that GATA6 is expressed in proliferating cells in the intestinal crypts and is required for crypt cell proliferation and migration 19,20 . Targeted inactivation of the GATA6 gene in mice causes early embryonic lethality due to the lack of endoderm differentiation [21][22][23] .…”

Transcription Factors GATA4 and HNF4A Control Distinct Aspects of Intestinal Homeostasis in Conjunction with Transcription Factor CDX2

“…1, C and D), although Gata6 loss was incomplete due to inefficient recombination at the Gata6 Fl allele (Fig. 1, D and E) (17). Thus, we refer to these mice as Gata4 del Cdx2 del and note that HNF4A expression was preserved (Fig.…”

“…Indeed, knock-out mice lacking single factors show diverse, subtle, and nonlethal defects. GATA4 and GATA6 show regional (proximal 4/5) and global intestinal expression, respectively, and the corresponding mutant mice have subtle defects in crypt cell replication, secretory cell differentiation, and control of selected enterocyte genes (15)(16)(17). Loss of HNF4A perturbs colon development (18), but Hnf4a Ϫ/Ϫ adult mouse intestines are overtly normal, with modestly perturbed gene expression (19).…”

Simultaneous Gene Deletion of Gata4 and Gata6 Leads to Early Disruption of Follicular Development and Germ Cell Loss in the Murine Ovary1

“…Conditional deletion of Gata6 and Gata4 produced a decrease in cellular proliferation in crypts of the small intestine [49] as well as a reduction in proliferating cell numbers in the pancreatic epithelium [50,51]. In addition, Gata4 is thought to regulate cardiomyocyte proliferation through direct activation of the Cyclin D2 and Cdk4 promoters [52], although this does not appear to be a general mechanism (Tevosian et al, unpublished results).…”