Determining the mechanisms regulating functional regionalization of the intestine

Medical College Of Wisconsin, Milwaukee WI

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Abstract

DESCRIPTION (provided by applicant): GATA4 is an essential regionalizing factor in the small intestinal epithelium. Loss of GATA4 from the jejunal epithelium shifts epithelial identity toward that of the ileum whereas ectopic expression of GATA4 in the ileum represses ileal identity and induces jejunal identity. GATA4 is also differentially expressed at another key boundary within the GI tract-the squamocolumnar junction-where it is expressed within the simple columnar epithelium of the glandular stomach but is absent from the stratified squamous epithelium of the esophagus/forestomach. This boundary is disrupted in Barrett's esophagus (BE), a premalignant metaplasia preceding esophageal adenocarcinoma (EAC). In BE, the stratified squamous epithelium of the esophagus is replaced by a columnar epithelium. The lack of expression of GATA4 in normal esophageal epithelium and its presence in areas of BE metaplasia along with the observation that the GATA4 gene is frequently amplified and expressed in EAC suggest a role for GATA4 in BE/EAC pathogenesis. Building from our studies of GATA4 in the small intestine, we hypothesize that exclusion of GATA4 from esophageal/ forestomach epithelium is essential for establishing the squamocolumnar junction and that GATA4 defines boundaries and confers regional-specific identity within the GI tract by repressing transcription. We will test our hypotheses using mouse and human models to manipulate GATA4 expression and function. In Aim 1, we will determine the role of GATA4 in defining the squamocolumnar junction. Our preliminary data showing conversion of a simple columnar epithelium toward a stratified squamous epithelium in GATA4-deficient hindstomach and conversion of a stratified squamous epithelium toward a simple columnar epithelium in GATA4-expressing forestomach support our hypothesis. We will manipulate GATA4 expression the context of a mouse BE model to assess the contribution of GATA4 to BE pathogenesis. We will also ectopically express GATA4 in human esophageal organoids to determine is GATA4 function at the squamocolumnar junction is conserved between mice and humans. In Aim 2, we will determine the molecular mechanisms through which GATA4 defines boundaries and confers regional specificity. We expect that studies of mice with altered GATA4 expression within the stomach and of human esophageal organoids expressing GATA4 will provide new models to study BE. These studies are significant because if our hypothesis is correct, we will identify GATA4 and its downstream targets as possible targets for future therapies and/or biomarkers for BE and other epithelial metaplasias.