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

Abstract

Mice that globally overexpress 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 overexpress Fra-2 specifically in these cell types (α-SMA-rtTA;tetO-Fra-2). Surprisingly, these mice did not develop vascular remodeling or pulmonary fibrosis but did develop 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-smooth muscle actin (SMA)-expressing fibroblasts (myofibroblasts) play a crucial role in this process. The mutant mice showed reduced numbers of secondary septa at postnatal day 7 and enlarged alveolae starting at postnatal day 12, suggesting impairment of secondary septa formation. 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 overexpression 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 overexpression 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.

• Authors: Kazuyuki Tsujino, John T Li, Tatsuya Tsukui, Xin Ren, Latifa Bakiri, Erwin Wagner, Dean Sheppard
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 313 Issue 5 Pg. L878-L888 (Nov 01 2017) ISSN: 1522-1504 [Electronic] United States
• PMID: 28818870 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 the American Physiological Society.

Chemical References

• Actins
• Fos-Related Antigen-2
• Fosl2 protein, mouse
• alpha-smooth muscle actin, mouse

Topics

• Actins (metabolism)
• Animals
• Animals, Newborn
• Fibroblasts (metabolism)
• Fos-Related Antigen-2 (metabolism)
• Lung (metabolism)
• Mice
• Myocytes, Smooth Muscle (metabolism)
• Myofibroblasts (metabolism)
• Pulmonary Alveoli (metabolism)
• Pulmonary Fibrosis (metabolism)