Universität zu Köln

Yin, Wenguang, Kim, Hyun-Taek, Wang, ShengPeng, Gunawan, Felix ORCID: 0000-0002-5592-9680, Li, Rui, Buettner, Carmen, Grohmann, Beate, Sengle, Gerhard, Sinner, Debora, Offermanns, Stefan and Stainier, Didier Y. R. (2019). Fibrillin-2 is a key mediator of smooth muscle extracellular matrix homeostasis during mouse tracheal tubulogenesis. Eur. Resp. J., 53 (3). SHEFFIELD: EUROPEAN RESPIRATORY SOC JOURNALS LTD. ISSN 1399-3003

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yin, Wenguang UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Hyun-Taek UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, ShengPeng UNSPECIFIED UNSPECIFIED UNSPECIFIED Gunawan, Felix UNSPECIFIED orcid.org/0000-0002-5592-9680 UNSPECIFIED Li, Rui UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Carmen UNSPECIFIED UNSPECIFIED UNSPECIFIED Grohmann, Beate UNSPECIFIED UNSPECIFIED UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Sinner, Debora UNSPECIFIED UNSPECIFIED UNSPECIFIED Offermanns, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Stainier, Didier Y. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-155199
DOI:	10.1183/13993003.00840-2018
Journal or Publication Title:	Eur. Resp. J.
Volume:	53
Number:	3
Date:	2019
Publisher:	EUROPEAN RESPIRATORY SOC JOURNALS LTD
Place of Publication:	SHEFFIELD
ISSN:	1399-3003
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BRANCHING MORPHOGENESIS; LUNG DEVELOPMENT; MARFAN-SYNDROME; CELL; CARTILAGE; MODEL; FIBRONECTIN; FBN2; EPITHELIUM; INSIGHTS Multiple languages Respiratory System Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15519