Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease

Hyun-Taek Kim (), Wenguang Yin, Young-June Jin, Paolo Panza, Felix Gunawan, Beate Grohmann, Carmen Buettner, Anna M. Sokol, Jens Preussner, Stefan Guenther, Sawa Kostin, Clemens Ruppert, Aditya M. Bhagwat, Xuefei Ma, Johannes Graumann, Mario Looso, Andreas Guenther, Robert S. Adelstein, Stefan Offermanns and Didier Y. R. Stainier ()
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Hyun-Taek Kim: Max Planck Institute for Heart and Lung Research
Wenguang Yin: Max Planck Institute for Heart and Lung Research
Young-June Jin: Max Planck Institute for Heart and Lung Research
Paolo Panza: Max Planck Institute for Heart and Lung Research
Felix Gunawan: Max Planck Institute for Heart and Lung Research
Beate Grohmann: Max Planck Institute for Heart and Lung Research
Carmen Buettner: Max Planck Institute for Heart and Lung Research
Anna M. Sokol: Max Planck Institute for Heart and Lung Research
Jens Preussner: Max Planck Institute for Heart and Lung Research
Stefan Guenther: Max Planck Institute for Heart and Lung Research
Sawa Kostin: Max Planck Institute for Heart and Lung Research
Clemens Ruppert: Biobank, University of Giessen & Marburg Lung Center (UGLMC)
Aditya M. Bhagwat: Weill Cornell Medicine - Qatar
Xuefei Ma: National Institutes of Health
Johannes Graumann: Max Planck Institute for Heart and Lung Research
Mario Looso: Max Planck Institute for Heart and Lung Research
Andreas Guenther: Biobank, University of Giessen & Marburg Lung Center (UGLMC)
Robert S. Adelstein: National Institutes of Health
Stefan Offermanns: Max Planck Institute for Heart and Lung Research
Didier Y. R. Stainier: Max Planck Institute for Heart and Lung Research

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06833-7

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