Fibrillin-2 is a key mediator of smooth muscle extracellular matrix homeostasis during mouse tracheal tubulogenesis

Abstract

Epithelial tubes, comprised of polarised epithelial cells around a lumen, are crucial for organ function. However, the molecular mechanisms underlying tube formation remain largely unknown. Here, we report on the function of fibrillin (FBN)2, an extracellular matrix (ECM) glycoprotein, as a critical regulator of tracheal tube formation. We performed a large-scale forward genetic screen in mouse to identify regulators of respiratory organ development and disease. We identified Fbn2 mutants which exhibit shorter and narrowed tracheas as well as defects in tracheal smooth muscle cell alignment and polarity. We found that FBN2 is essential for elastic fibre formation and Fibronectin accumulation around tracheal smooth muscle cells. These processes appear to be regulated at least in part through inhibition of p38-mediated upregulation of matrix metalloproteinases (MMPs), as pharmacological decrease of p38 phosphorylation or MMP activity partially attenuated the Fbn2 mutant tracheal phenotypes. Analysis of human tracheal tissues indicates that a decrease in ECM proteins, including FBN2 and Fibronectin, is associated with tracheomalacia. Our findings provide novel insights into the role of ECM homeostasis in mesenchymal cell polarisation during tracheal tubulogenesis.

Lessons from tracheal tube development for understanding congenital tracheal malformations

“…YIN et al [18] also connect the findings obtained with the Fbn2 mutant mice with individuals suffering from tracheomalacia. Fibrillin-2 levels are reduced in the ventral parts of the trachea obtained from patients.…”

“…Presumably, fibrillin-1 in these tissues can rescue the functions of fibrillin-2. In the vasculature, loss of fibrillin-1 in Fbn1 −/− mice results in similar phenotypes to those of the trachea in Fbn2 mutant mice, with smooth muscle cell disorientation, upregulation of p38 MAPK and MMP levels, and elastin degradation due to a loss of contact between the cells and the matrix [18,22,23]. Altogether, these data illustrate that fibrillin-1 can fully compensate for the loss of fibrillin-2 in the vasculature and the oesophagus, whereas cell and tissue deficiencies can develop in the trachea, presumably due to the absence of fibrillin-1.…”

“…It is interesting that the role of fibrillin-2 is specific for tracheal tube development and is not observed in other organ tube development. YIN et al [18] have shown the absence of a phenotype in the oesophagus of the Fbn2 mutant mice, which also expresses fibrillin-1. Previous studies have demonstrated the absence of a phenotype in the vasculature of Fbn2 null mice in the presence of fibrillin-1 [22].…”

“…In the current issue of the European Respiratory Journal, YIN et al [18] have employed forward genetic screening and analysis in mice to identify novel functions of fibrillin-2 in tracheal tubulogenesis (figure 1). In this study, loss of fibrillin-2 resulted in compromised tracheal tubulogenesis, characterised by a shortened tracheal tube as well as fewer and fragmented cartilage rings.…”

“…The study by YIN et al [18] also deciphers a function of fibrillin-2 in the regulation of smooth muscle cell orientation and polarity in the trachea. The authors demonstrate that p38 mitogen-activated protein kinase (MAPK)-mediated downregulation of matrix metalloproteinases (MMPs) is instrumental for this function.…”