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

ABSTRACT: 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. 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 (Gata4 D-CKO) die after birth with abnormal diaphragm formation and lung hypoplasia thus we focused on the latest stage of embryonic development. We obtained whole lung RNA at embryonic day 18 (E18) at the latest stage prior to delivery due to early postnatal death of Gata4 D-CKO mice. We performed bulk RNA sequencing on control embryos (termed Gata4 D-control, Prx1Cre;Gata4F/+) and embryos with diaphragm-specific inactivation of Gata4 (termed Gata4 D-CKO, Prx1Cre;Gata4F/D). In this bulk RNA sequencing dataset are expression data from Gata4 D-control and D-CKO whole lungs at E18 implicating abnormal expression of genes involved in cell cycling and motor protein pathways. Mechanical compression of the embryonic lungs was also associated with 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE324576 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Two critical events that are required for normal transition from fetal to extrauterine life are development of the alveoli that allow for efficient gas exchange in the lung and relaxation of the pulmonary vascular smooth muscle. Patients with congenital diaphragmatic hernia (CDH) have abnormal lung and pulmonary vascular development that results in a lethal combination of lung hypoplasia and pulmonary hypertension. To better understand the mechanisms responsible for abnormal lung and pulmonary vascular development and function we generated Pbx1/2 conditional knockout mice that lack Pbx1 and Pbx2 expression in the lung mesenchyme. Pbx1 has previously been shown to be required for normal diaphragm development, however its role in alveologenesis, and the mechanisms responsible for pulmonary hypertension, has not been studied. We found that Pbx1/2 CKO mice have failure of alveologenesis and die of severe pulmonary hypertension by 2 to 3 weeks of age. In order to better understand the downstream genetic mis-regulation caused by deletion of Pbx1/2, and identify their potential transcriptional targets, we carried out transcriptional profiling of Pbx1/2 CKO and control mice starting at postnatal day 3 (P3), when a histological phenotype first becomes apparent, and then working back to the time of birth (P0), and embryonic day 14 (E14) when the pulmonary vascular smooth muscle is developing. In this dataset are the expression data obtained from dissected embryonic and early postnatal lungs of Pbx1/2 CKO and control mice. Pbx1/2 CKO mice are homozygous null for Pbx2 with conditional deletion of Pbx1 in the lung mesenchyme directed by Tbx4 Cre (Tbx4 Cre/wild-type; Pbx1 flox/flox; Pbx2 delta/delta). Control mice are homozygous null for Pbx2 and are heterozygous for Pbx1 in the lung mesenchyme (Tbx4 Cre/wild-type; Pbx1 flox/wild-type; Pbx2 delta/delta). These data are used to identify the transcriptional targets and down-stream effectors of PBX transciptional regulation in the lung.

Project description:BACKGROUND: Congenital diaphragmatic hernia (CDH) is characterized by a diaphragmatic defect, leading to herniation of abdominal organs into the chest, lung compression, and impaired lung development, often resulting in pulmonary hypertension and lung hypoplasia. Prenatal imaging techniques like ultrasound and MRI provide anatomical predictors of outcomes, but their limitations necessitate novel biomarkers for better prognostic accuracy. OBJECTIVE: This study aims to identify unique circulating maternal, fetal, and neonatal microRNAs (miRNAs) that can distinguish CDH pregnancies from healthy controls and assess their potential as markers of disease severity. STUDY DESIGN: We conducted a prospective study involving third-trimester maternal blood, amniotic fluid, cord blood, and neonatal blood samples from pregnancies complicated by CDH and healthy controls. miRNA expression was analyzed using RNA-sequencing, and random forest analysis identified miRNAs distinguishing CDH survivors from nonsurvivors. Pathway enrichment analyses were performed to explore the biological relevance of differentially expressed miRNAs. RESULTS: Significant miRNA expression differences were observed between CDH and control samples across all sample types. In infant blood, 148 miRNAs were up-regulated, and 36 were down-regulated in CDH cases. Pathway analysis revealed that dysregulated miRNAs in CDH targeted pathways related to protein binding, transcription regulation, and signaling pathways implicated in pulmonary hypertension and lung hypoplasia. Random forest analysis identified miRNAs in maternal blood (miR-7850-5p_L-1R+2, miR-942-3p, and miR-197-3p) that distinguished CDH survivors from nonsurvivors, with an receiver operating characteristic area under the curve of 1.0. CONCLUSION: Circulating miRNAs in maternal blood offer promising biomarkers for predicting CDH outcomes. miRNAs from infant blood provide mechanistic insights and potential targets for therapeutic intervention in critical pathways of pulmonary hypertension and lung hypoplasia. Further studies with larger cohorts are needed to validate these findings and explore the clinical application of miRNA biomarkers in CDH management.

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

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