A critical role for miR-142 in alveolar epithelial lineage formation

Abstract

The development of a functional lung, capable of gas exchange, requires proper alveologenesis. Mechanisms regulating AT1 and AT2 cell maturation are poorly defined. We report the activation of the glucocorticoid pathway in an in vitro alveolar epithelial lineage differentiation assay led to increased AT2 marker Sftpc and decreased miR-142 expression. Using a constitutive KO mouse model, we further demonstrate a relative increase of AT2 and a decrease in AT1 cell number with a global decrease of AT2 gene profile signature in miR-142 KO AT2 cells. Over-expression of miR-142 in alveolar progenitor cells in vivo led to an opposite effect. Examination of the KO lungs at E18.5, revealed enhanced expression miR-142 targets like Apc, Ep300 and Kras associated with increased Ctnnb1 and p-Erk signaling. Pharmacological inhibition of Ep300-Ctnnb1 in vitro prevented an increase in Sftpc expression triggered by loss of miR-142. These results together suggest glucocorticoid-miR-142-p300 signaling axis controls pneumocyte maturation.