Background & Aims GATA transcription factors regulate genes in multiple organs to control proliferation and differentiation. GATA4 is expressed in the proximal 85% of the small intestine, where it regulates the expression of genes that are specifically expressed by absorptive enterocytes. GATA6 is co-expressed with GATA4 but is also expressed in the ileum; its function in the mature small intestine is unknown. Methods We investigated the function of GATA6 in small intestine using adult mice with inducible disruption of Gata6, or Gata6 and Gata4, specifically in the intestine. Results In ileum, deletion of Gata6 reduced in proliferation and numbers of enteroendocrine cells, increased numbers of goblet-like cells in crypts, caused loss of Paneth cells, and altered expression of genes specific to absorptive enterocytes. In contrast, in jejunum and duodenum, deletion of Gata6 increased numbers of Paneth cells. Deletion of Gata6 and Gata4 resulted jejunal and duodenal phenotype that was nearly identical to that in the ileum after deletion of Gata6 alone, demonstrating that most GATA4 functions are redundant with those of GATA6. Conclusion GATA transcription factors are required for proliferation, secretory cell differentiation, and expression of genes by absorptive enterocytes in the small intestinal epithelium.

In many mammalian species, the intestinal epithelium undergoes major changes that allow a dietary transition from mother's milk to the adult diet at the end of the suckling period. These complex developmental changes are the result of a genetic programme intrinsic to the gut tube, but its regulators have not been identified. Here we show that transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1) is highly expressed in the developing and postnatal intestinal epithelium until the suckling to weaning transition. Intestine-specific deletion of Blimp1 results in growth retardation and excessive neonatal mortality. Mutant mice lack all of the typical epithelial features of the suckling period and are born with features of an adult-like intestine. We conclude that the suckling to weaning transition is regulated by a single transcriptional repressor that delays epithelial maturation.

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.