MicroRNA in late lung development and bronchopulmonary dysplasia: the need to demonstrate causality

MicroRNA are emerging as powerful regulators of cell differentiation and tissue and organ development. Several microRNA have been described to play a role in branching morphogenesis, a key step in early lung development. However, considerably less attention has been paid to microRNA as regulators of the process of secondary septation, which drives lung alveolarization during late lung development. Secondary septation is severely perturbed in bronchopulmonary dysplasia (BPD), a common complication of preterm birth characterized by blunted alveolarization. A number of studies to date have reported microRNA microarray screens in animal models of BPD; however, only two studies have attempted to demonstrate causality. Although the expression of miR-150 was altered in experimental BPD, a miR-150(-/-) knockout mouse did not exhibit appreciable protection in a BPD animal model. Similarly, while the expression of miR-489 in the lung was reduced in clinical and experimental BPD, antagomiR and over-expression approaches could not validate a role for miR-489 in the impaired alveolarization associated with experimental BPD. This mini-review aims to highlight microRNA that have been revealed by multiple microarray studies to be potential causal players in normal and pathological alveolarization. Additionally, the challenges faced in attempting to demonstrate a causal role for microRNA in lung alveolarization are discussed. These include the tremendous variability in the animal models employed, and the limitations and advantages offered by the available tools, including antagomiRs and approaches for the validation of a specific microRNA-mRNA interaction during lung alveolarization.