GATA Factors Regulate Proliferation, Differentiation, and Gene Expression in Small Intestine of Mature Mice

doi:10.1053/j.gastro.2011.01.033

Gastroenterology

Volume 140, Issue 4, April 2011, Pages 1219-1229.e2

https://doi.org/10.1053/j.gastro.2011.01.033 Get rights and content

Background & Aims

GATA transcription factors regulate proliferation, differentiation, and gene expression in multiple organs. GATA4 is expressed in the proximal 85% of the small intestine and regulates the jejunal-ileal gradient in absorptive enterocyte gene expression. GATA6 is co-expressed with GATA4 but also is 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 conditional, inducible deletion of Gata6, or Gata6 and Gata4, specifically in the intestine.

Results

In ileum, deletion of Gata6 caused a decrease in crypt cell proliferation and numbers of enteroendocrine and Paneth cells, an increase in numbers of goblet-like cells in crypts, and altered expression of genes specific to absorptive enterocytes. In contrast to ileum, deletion of Gata6 caused an increase in numbers of Paneth cells in jejunum and ileum. Deletion of Gata6 and Gata4 resulted in a jejunal and duodenal phenotype that was nearly identical to that in the ileum after deletion of Gata6 alone, revealing common functions for GATA6 and GATA4.

Conclusions

GATA transcription factors are required for crypt cell proliferation, secretory cell differentiation, and absorptive enterocyte gene expression in the small intestinal epithelium.

Section snippets

Mice

Previously established and confirmed Gata6^loxP/loxP, Gata4^flap/flap, and transgenic VillinCreER^T2 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. Gata6^loxP/loxP, VillinCreER^T2-positive (G6del), Gata6^loxP/loxP, Gata4^flap/flap, VillinCreER^T2-positive (G6G4del), and Gata6^loxP/loxP, VillinCreER^T2-negative or Gata6^Wt/Wt, VillinCreER^T2-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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: 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.

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Basic—Alimentary TractGATA Factors Regulate Proliferation, Differentiation, and Gene Expression in Small Intestine of Mature Mice

Background & Aims

Methods

Results

Conclusions

Section snippets

Mice

Intestinal Gata6 Deletion Results in a Reduction in Villus Length, Villus Epithelial Cell Number, and Crypt Proliferation in Ileum

Discussion

Acknowledgments

Curr Opin Cell Biol

Gastroenterology

Cell

J Biol Chem

J Biol Chem

Gastroenterology

Dev Biol

Cell

Gastroenterology

Exp Cell Res

Blood

J Biol Chem

Dev Biol

Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4

Nat Genet

Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1

Proc Natl Acad Sci U S A

Canonical Wnt signals are essential for homeostasis of the intestinal epithelium

Genes Dev

Crypt-restricted proliferation and commitment to the Paneth cell lineage following Apc loss in the mouse intestine

Development

Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine

Development

Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2

EMBO Rep

Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells

Nature

Basic—Alimentary Tract
GATA Factors Regulate Proliferation, Differentiation, and Gene Expression in Small Intestine of Mature Mice