Basic—Alimentary TractGATA Factors Regulate Proliferation, Differentiation, and Gene Expression in Small Intestine of Mature Mice
Section snippets
Mice
Previously established and confirmed Gata6loxP/loxP, Gata4flap/flap, and transgenic VillinCreERT2 mice16, 20, 22, 23 were used in this study to produce conditional, inducible deletion of Gata6 or both Gata6 and Gata4 in the intestinal epithelium. Gata6loxP/loxP, VillinCreERT2-positive (G6del), Gata6loxP/loxP, Gata4flap/flap, VillinCreERT2-positive (G6G4del), and Gata6loxP/loxP, VillinCreERT2-negative or Gata6Wt/Wt, VillinCreERT2-positive (control) mice, 6–8 weeks of age, were treated with
Intestinal Gata6 Deletion Results in a Reduction in Villus Length, Villus Epithelial Cell Number, and Crypt Proliferation in Ileum
GATA6 was expressed in all differentiated and proliferating cells in the mature mouse small intestinal epithelium, with the highest staining intensity in the proliferative crypt compartment (Supplementary Figure 2). To determine the function of GATA6 in this tissue, a tamoxifen-inducible, intestine-specific Gata6 deletion model (G6del) was established (Supplementary Figure 3). Mice killed up to 4 weeks after Gata6 deletion showed normal growth and activity; in a cohort of male mice, body
Discussion
We previously showed that GATA4 specifically regulates jejuno–ileal differences in absorptive enterocyte gene expression and function.16, 22 Here, we show that in ileum, where Gata6 is expressed but Gata4 is not, conditional deletion of Gata6 results in a decrease in cellular proliferation in crypts, a decrease in enteroendocrine cell allocation, a conversion of Paneth cells into goblet-like cells at the base of crypts, and an alteration in the expression of specific absorptive enterocyte genes
Acknowledgments
The authors thank Ms M. P. Flanagan for technical support, Dr S. Hagan and A. Calhoun for technical assistance and insight with electron microscopy, Dr H. Clevers for samples from the Spdef knockout mice, Dr P. A. Dawson and Ms J. Haywood for valuable insight and technical support, Dr A. J. Ouellette for the alpha-defensin related sequence and alpha-defensin 1 antibodies, Dr D. K. Podolsky for the trefoil factor 3 antibody, Dr J. Whitsett for the SAM pointed domain containing ets transcription
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2022, Journal of Biological ChemistryCitation Excerpt :Among these, CDX2 is viewed as a master regulator of intestinal epithelial cell identity (24) that maintains a permissive chromatin environment that favorably influences the DNA binding of other TFs, for example, the intestine restricted TF HNF4a (25). Similarly, SMAD4 and HNF4 activate each other's expression and cobind to regulatory elements of intestinal differentiation genes to stabilize enterocyte identity (26), whereas other evidence shows that GATA4 is critical for gene expression in the proximal small intestine (27). However, the established role for these TFs neither precludes a role for other TFs in the small intestine nor does explain the regulation in the colon, where GATA4 is absent (28).
Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE22416).
Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants RO3-DK-84167 (N.F.S.), RO1-DK-055743 (S.A.D.), RO1-DK-066226 (S.A.D.), RO1-DK-054111 (J.C.F.), and RO1-DK-061382 (S.D.K.); Harvard Digestive Disease Center grant 5P30-DK-34854; National Cancer Institute grant RO1-CA-142826 (N.F.S.); the Nutricia Research Foundation (E.B.); the Foundation De Drie Lichten (E.B.); and the Foundation Doctor Catharine van Tussenbroek (E.B.) in The Netherlands.