Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia

Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA ( are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several in BPD, a causal role remains to be established. Our results showed that the expression level of increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of in alveolar type 2 cells (AT2). We hypothesized that the decrease in expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based overexpression. Maintenance of expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified as a key downstream target of . Caveolin1 protein is downregulated in response to overexpression of . This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing display decreased expression of AT2 markers and increased expression of AT1 markers. Our results suggest that down-regulation of in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification.