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 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Cells Année : 2020

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

L'incapacité à réguler à la baisse l'expression de miR-154 dans l'épithélium pulmonaire postnatal précoce de la souris supprime l'alvéologénèse, avec des modifications de la signalisation Tgf-β similaires à celles induites par l'exposition à l'hyperoxie

Jin Wu
Adriana Contreras

Résumé

Background: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR in BPD, a causal role remains to be established. Results: Our results showed that the expression level of miR-154 increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of miR-154 in alveolar type 2 cells (AT2). We hypothesized that the decrease in miR-154 expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based miR-154 overexpression. Maintenance of miR-154 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 Caveolin1 as a key downstream target of miR-154. Caveolin1 protein is downregulated in response to overexpression of miR-154. This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing miR-154 display decreased expression of AT2 markers and increased expression of AT1 markers. Conclusion: Our results suggest that down-regulation of miR-154 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 miR-154 suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification.
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Dates et versions

hal-03438483 , version 1 (23-11-2021)

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Cho-Ming Chao, Gianni Carraro, Zvonimir Rako, Johannes Kolck, Jamschid Sedighi, et al.. 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. Cells, 2020, 9 (4), pp.859. ⟨10.3390/cells9040859⟩. ⟨hal-03438483⟩
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