Fra-2 negatively regulates postnatal alveolar septation by modulating myofibroblast function

Mice that globally over-express the transcription factor, Fos-related antigen-2 (Fra-2), develop extensive pulmonary fibrosis and pulmonary vascular remodeling. To determine if these phenotypes are a consequence of ectopic Fra-2 expression in vascular smooth muscle cells and myofibroblasts, we generated mice that over-express Fra-2 specifically in these cells types (α-SMA-rtTA; tetO-Fra-2). Surprisingly, these mice did not develop vascular remodeling or pulmonary fibrosis, but developed a spontaneous emphysema-like phenotype characterized by alveolar enlargement. Secondary septa formation is an important step in the normal development of lung alveoli and α-SMA expressing fibroblasts (myofibroblasts) play a crucial role in this process. The mutant mice showed reduced numbers of secondary septa at P7 and enlarged alveolar size starting at P12, suggesting that the process of secondary septa formation was impaired. Lineage tracing using α-SMA-rtTA mice crossed to a floxed TdTomato reporter revealed that embryonic expression of α-SMA cre marked a population of cells that gave rise to nearly all alveolar myofibroblasts. Comprehensive transcriptome analyses (RNA sequencing) demonstrated that the overwhelming majority of genes whose expression was significantly altered by over-expression of Fra-2 in myofibroblasts encoded secreted proteins, components of the extracellular matrix (ECM) and cell adhesion associated genes, including coordinate upregulation of pairs of integrins and their principal ECM ligands. In addition, primary myofibroblasts isolated from the mutant mice showed reduced migration capacity. These findings suggest that Fra-2 over-expression might impair myofibroblast functions crucial for secondary septation, such as myofibroblast migration across alveoli, by perturbing interactions between integrins and locally produced components of the ECM.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2w7lRxt
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