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-2 (FBN2), 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 (SM) cell alignment and polarity. We found that FBN2 is essential for elastic fiber formation and Fibronectin accumulation around tracheal SM 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.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Yin has nothing to disclose.
Conflict of interest: Dr. Kim has nothing to disclose.
Conflict of interest: Dr. Wang has nothing to disclose.
Conflict of interest: Dr. Gunawan has nothing to disclose.
Conflict of interest: Dr. Li has nothing to disclose.
Conflict of interest: Dr. Buettner has nothing to disclose.
Conflict of interest: Dr. Grohmann has nothing to disclose.
Conflict of interest: Dr. Sengle has nothing to disclose.
Conflict of interest: Dr. Sinner has nothing to disclose.
Conflict of interest: Dr. Offermanns has nothing to disclose.
Conflict of interest: Dr. Stainier has nothing to disclose.
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