Mechanical Compression Causes Lung Hypoplasia in Congenital Diaphragmatic Hernia with GATA4 Genetic Variants

Congenital diaphragmatic hernia (CDH) is a common and severe structural malformation in which the high rate of morbidity and mortality is caused by lung hypoplasia and pulmonary hypertension. Severity of lung and pulmonary vascular defects in patients with CDH is heterogeneous with both intrinsic defects during development and mechanical compression playing important roles. Genetic variants have been identified in 30% of CDH patients and are associated with increased morbidity and mortality but it is unclear how these variants impact lung and pulmonary vascular defect severity. Deletions of 8p23.1 account for 3-5% of cases and encompass GATA4, a transcription factor that directs gene expression throughout the developing embryo. CDH patients with GATA4 haploinsufficiency have high mortality and severe lung hypoplasia and pulmonary hypertension. Given this information, our aim was to characterize the role of GATA4 during lung and pulmonary vascular development. We generated mice with lung-specific deletion of Gata4 and found that GATA4 is not required during lung or pulmonary vascular development. However, mice with diaphragm-specific inactivation of Gata4 die after birth with abnormal diaphragm formation and lung hypoplasia. Mechanical compression of the embryonic lungs was associated with abnormal gene expression and increased phosphorylation of mechanosensory protein YAP1 resulting in decreased cell cycling. Our data suggest that the lung and pulmonary vascular phenotype of patients with CDH and GATA4 haploinsufficiency is due to mechanical compression. Strategies that promote lung growth prior to delivery such as fetal tracheal occlusion may be beneficial in these patients.