Abstract
miR-200b plays a role in epithelial-to-mesenchymal transition (EMT) in cancer. We recently reported abnormal expression of miR-200b in the context of human pulmonary hypoplasia in congenital diaphragmatic hernia (CDH). Smaller lung size, a lower number of airway generations, and a thicker mesenchyme characterize pulmonary hypoplasia in CDH. The aim of this study was to define the role of miR-200b during lung development. Here we show that miR-200b−/− mice have abnormal lung function due to dysfunctional surfactant, increased fibroblast-like cells and thicker mesenchyme in between the alveolar walls. We profiled the lung transcriptome in miR-200b−/− mice, and, using Gene Ontology analysis, we determined that the most affected biological processes include cell cycle, apoptosis and protein transport. Our results demonstrate that miR-200b regulates distal airway development through maintaining an epithelial cell phenotype. The lung abnormalities observed in miR-200b−/− mice recapitulate lung hypoplasia in CDH.
Highlights
Every year, over 50,000 children are born with congenital diaphragmatic hernia (CDH) associated with abnormal lung development resulting in lung hypoplasia and persistent pulmonary hypertension[1,2,3]
We found that higher miR-200b expression in the fetal tracheal fluid of CDH fetus is associated with a better response to fetoscopic endoluminal tracheal occlusion (FETO, a prenatal therapy to promote lung growth)[16]
We showed that mature microRNAs transcribed in the same cluster - miR-200a and miR-429 - were still expressed, albeit lower compared to miR200b+/+ lungs (Fig. 1f, Supplementary Fig. 5)
Summary
Over 50,000 children are born with congenital diaphragmatic hernia (CDH) associated with abnormal lung development resulting in lung hypoplasia and persistent pulmonary hypertension[1,2,3]. MicroRNAs (miRNA) are small, non-coding RNAs that regulate gene expression through mRNA stability and translation[8,9,10]. They are essential for development and homeostasis of organs[11,12,13,14]. Others have shown that miR200 is down-regulated in a mouse model of fibrotic lung disease and human patients with idiopathic pulmonary fibrosis (IPF)[21]. The goal of this study was to delineate the role of miR-200b during lung development using loss of function models in vivo. MiR-200b deficient mice had stiffer lungs due to disturbed distal airway branching, thicker alveolar walls and downregulation of epithelial cell differentiation. Our data suggest that miR-200b is required to achieve the necessary balance in development of lung epithelial cells and fibroblasts to ensure development of a structurally and functionally effective respiratory organ
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