GATA4 Controls Epithelial Morphogenesis in the Developing Stomach to Promote Establishment of Glandular Columnar Epithelium. Cell Mol Gastroenterol Hepatol 2021;12(4):1391-1413
Date
06/11/2021Pubmed ID
34111600Pubmed Central ID
PMC8479485DOI
10.1016/j.jcmgh.2021.05.021Scopus ID
2-s2.0-85115766757 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
BACKGROUND & AIMS: The transcription factor GATA4 is broadly expressed in nascent foregut endoderm. As development progresses, GATA4 is lost in the domain giving rise to the stratified squamous epithelium of the esophagus and forestomach (FS), while it is maintained in the domain giving rise to the simple columnar epithelium of the hindstomach (HS). Differential GATA4 expression within these domains coincides with the onset of distinct tissue morphogenetic events, suggesting a role for GATA4 in diversifying foregut endoderm into discrete esophageal/FS and HS epithelial tissues. The goal of this study was to determine how GATA4 regulates differential morphogenesis of the mouse gastric epithelium.
METHODS: We used a Gata4 conditional knockout mouse line to eliminate GATA4 in the developing HS and a Gata4 conditional knock-in mouse line to express GATA4 in the developing FS.
RESULTS: We found that GATA4-deficient HS epithelium adopted a FS-like fate, and conversely, that GATA4-expressing FS epithelium adopted a HS-like fate. Underlying structural changes in these epithelia were broad changes in gene expression networks attributable to GATA4 directly activating or repressing expression of HS or FS defining transcripts. Our study implicates GATA4 as having a primary role in suppressing an esophageal/FS transcription factor network during HS development to promote columnar epithelium. Moreover, GATA4-dependent phenotypes in developmental mutants reflected changes in gene expression associated with Barrett's esophagus.
CONCLUSIONS: This study demonstrates that GATA4 is necessary and sufficient to activate the development of simple columnar epithelium, rather than stratified squamous epithelium, in the embryonic stomach. Moreover, similarities between mutants and Barrett's esophagus suggest that developmental biology can provide insight into human disease mechanisms.
Author List
DeLaForest A, Kohlnhofer BM, Franklin OD, Stavniichuk R, Thompson CA, Pulakanti K, Rao S, Battle MAAuthor
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBinding Sites
Biomarkers
Esophagus
GATA4 Transcription Factor
GATA6 Transcription Factor
Gastric Mucosa
Gene Expression Profiling
Gene Expression Regulation, Developmental
Immunohistochemistry
Mice
Mice, Knockout
Morphogenesis
Organogenesis
Protein Binding
