The Role of GATA4 in Lung Hypoplasia and Pulmonary Hypertension Associated with CDH

Betty N. Pham, University of California, San Diego School of Medicine, United States; Giangela M. Stokes, University of California, San Diego School of Medicine, United States; Mark Wienhold, University of Wisconsin-Madison, United States; Rebecca Hernan, Columbia University, United States; Wendy Chung, Columbia University, United States; David McCulley, University of California, San Diego School of Medicine, San Diego, CA, United States

Background: Congenital diaphragmatic hernia (CDH) is a common and severe structural malformation affecting 5/10,000 births with a 10-50% mortality rate. The range in mortality is due to varying severity of lung hypoplasia and pulmonary hypertension. Our hypothesis is that genomic variants are responsible for CDH and play a central role in lung and pulmonary vascular development. Identifying variants in patients might improve accuracy of prognosis and guide individual treatment. The transcription factor GATA4 is expressed in the developing diaphragm, lungs, and pulmonary vasculature. Variants causing GATA4 loss-of-function (LOF) are among the most common in CDH patients. Although GATA4 is required for diaphragm development, its role in lung and pulmonary vascular development is unclear. Among 9 CDH patients with GATA4 LOF variants, the mortality rate was 67%. Of the survivors, the majority required oxygen and pulmonary vasodilator medications at discharge. Our hypothesis was that GATA4 directs lung and pulmonary vascular development and that GATA4 LOF causes lung hypoplasia and pulmonary hypertension independent of its role in diaphragm development.

Objectives: To determine the role of GATA4 in lung and pulmonary vascular development.

Design/Methods: Using a tissue-specific, conditional gene deletion approach in mice, we inactivated Gata4 expression in the developing lung mesenchyme. We used histology, gene expression analysis, and physiology testing to analyze the mutant phenotype.

Results: In contrast to what has been reported previously, Gata4 deletion in the lung mesenchyme did not impact branching morphogenesis or alveologenesis. Epithelial cell development was normal in Gata4 conditional deletion (Gata4 CKO) mice. Furthermore, pulmonary vascular development was similar between wildtype and Gata4 CKO mice with no pulmonary hypertension.

Conclusion: Despite the high mortality rate, persistent respiratory distress, and pulmonary hypertension phenotype in CDH patients with GATA4 LOF gene variants, conditional deletion of GATA4 in mice did not impact lung or pulmonary vascular development. These data are important because they suggest that lung and pulmonary vascular defects in these patients are due to mechanical compression during development. CDH patients with GATA4 LOF variants may be ideal candidates for fetal procedures, like tracheal occlusion, that address mechanical compression to improve lung development.