GATA4 and GATA6 regulate intestinal epithelial cytodifferentiation during development. Dev Biol 2014 Aug 15;392(2):283-94
Date
06/15/2014Pubmed ID
24929016Pubmed Central ID
PMC4149467DOI
10.1016/j.ydbio.2014.05.017Scopus ID
2-s2.0-84904397909 (requires institutional sign-in at Scopus site) 57 CitationsAbstract
The intestinal epithelium performs vital roles in organ function by absorbing nutrients and providing a protective barrier. The zinc-finger containing transcription factors GATA4 and GATA6 regulate enterocyte gene expression and control regional epithelial cell identity in the adult intestinal epithelium. Although GATA4 and GATA6 are expressed in the developing intestine, loss of either factor alone during the period of epithelial morphogenesis and cytodifferentiation fails to disrupt these processes. Therefore, we tested the hypothesis that GATA4 and GATA6 function redundantly to control these aspects of intestinal development. We used Villin-Cre, which deletes specifically in the intestinal epithelium during the period of villus development and epithelial cytodifferentiation, to generate Gata4Gata6 double conditional knockout embryos. Mice lacking GATA4 and GATA6 in the intestinal epithelium died within 24h of birth. At E18.5, intestinal villus architecture and epithelial cell populations were altered. Enterocytes were lost, and goblet cells were increased. Proliferation was also increased in GATA4-GATA6 deficient intestinal epithelium. Although villus morphology appeared normal at E16.5, the first time at which both Gata4 and Gata6 were efficiently reduced, changes in expression of markers of enterocytes, goblet cells, and proliferative cells were detected. Moreover, goblet cell number was increased at E16.5. Expression of the Notch ligand Dll1 and the Notch target Olfm4 were reduced in mutant tissue indicating decreased Notch signaling. Finally, we found that GATA4 occupies chromatin near the Dll1 transcription start site suggesting direct regulation of Dll1 by GATA4. We demonstrate that GATA4 and GATA6 play an essential role in maintaining proper intestinal epithelial structure and in regulating intestinal epithelial cytodifferentiation. Our data highlight a novel role for GATA factors in fine tuning Notch signaling during intestinal epithelial development to repress goblet cell differentiation.
Author List
Walker EM, Thompson CA, Battle MAMESH terms used to index this publication - Major topics in bold
AnimalsCalcium-Binding Proteins
Cell Differentiation
Chromatin Immunoprecipitation
Fluorescent Antibody Technique
GATA4 Transcription Factor
GATA6 Transcription Factor
Gene Expression Regulation, Developmental
Immunohistochemistry
Intercellular Signaling Peptides and Proteins
Intestinal Mucosa
Mice
Mice, Knockout
Oligonucleotide Array Sequence Analysis
Receptors, Notch
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
