Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease

  • Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is downregulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.
Metadaten
Author:Hyun-Taek Kim, Wenguang Yin, Young-June Jin, Paolo Panza, Felix GunawanORCiD, Beate Grohmann, Carmen Büttner, Anna Sokol, Jens PreussnerORCiDGND, Stefan GüntherORCiD, Sawa Kostin, Clemens Ruppert, Aditya M. Bhagwat, Xuefei Ma, Johannes Graumann, Mario LoosoORCiDGND, Andreas GüntherORCiDGND, Robert S. Adelstein, Stefan OffermannsORCiDGND, Didier StainierORCiD
URN:urn:nbn:de:hebis:30:3-501219
DOI:https://doi.org/10.1038/s41467-018-06833-7
ISSN:2041-1723
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30389913
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/11/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/04/29
Tag:Developmental biology; Extracellular matrix; Respiratory tract diseases
Volume:9
Issue:1, Art. 4600
Page Number:13
First Page:1
Last Page:13
Note:
Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
HeBIS-PPN:450964833
Institutes:Biowissenschaften / Biowissenschaften
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0