# GATA4 in development of a normal squamocolumnar junction and Barretts esophagus

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $426,104

## Abstract

Project Summary
Reactivation of pathways used during embryonic development to pattern and specify tissue fate and function
can play a role in disease. This proposal explores the idea that abnormal re-activation of the developmentally
important transcription factor GATA4 in the stratified epithelium of the esophagus contributes to the pathology
of Barrett's esophagus (BE), a premalignant metaplasia of the esophagus. Individuals with BE have an
elevated lifetime risk of developing esophageal adenocarcinoma (EAC), a deadly cancer with a five-year
survival rate of only ~18%. As the most widely recognized EAC risk factor, BE is a critical target for the
development of therapies that can reduce BE and thereby esophageal cancer. Our previous work
demonstrates that GATA4, which is expressed in the jejunum but absent in the ileum of the small intestine, is
essential to pattern the jejunal-ileal boundary. GATA4 is also differentially expressed at the squamocolumnar
junction, where it is present within the columnar epithelium of the glandular stomach but absent from the
stratified squamous epithelium of the esophagus/forestomach. In BE, this boundary is disrupted with the
stratified squamous epithelium of the esophagus being replaced by columnar epithelium. The lack of GATA4
expression 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 pathogenesis. Moreover, acid and bile, two gastroesophageal reflux components implicated as having key
roles in BE development, induce GATA4 expression in adult human esophageal squamous cells. We
hypothesize that exclusion of GATA4 from esophageal/forestomach epithelium is essential to establish a
normal squamocolumnar junction during development and that re-activation of GATA4 in stratified epithelium in
the setting of reflux-induced inflammation contributes to development of Barrett's esophagus. We will test our
hypotheses using unique 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 during development. Our
preliminary data showing conversion of columnar epithelium to stratified epithelium in GATA4-deficient
hindstomach and conversion of stratified epithelium to columnar epithelium in GATA4-expressing forestomach
support our hypothesis. In Aim 2, we will determine how re-activation of GATA4 in stratified epithelium in the
setting of reflux-induced inflammation contributes to the pathogenesis of Barrett's esophagus. 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 to interrogate for
future therapies and/or as biomarkers for...

## Key facts

- **NIH application ID:** 9968303
- **Project number:** 5R01DK111822-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** MICHELE A BATTLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $426,104
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968303

## Citation

> US National Institutes of Health, RePORTER application 9968303, GATA4 in development of a normal squamocolumnar junction and Barretts esophagus (5R01DK111822-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9968303. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*