RT Journal Article SR Electronic T1 Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease JF bioRxiv FD Cold Spring Harbor Laboratory SP 414268 DO 10.1101/414268 A1 Hyun-Taek Kim A1 Wenguang Yin A1 Young-June Jin A1 Paolo Panza A1 Felix Gunawan A1 Beate Grohmann A1 Carmen Buettner A1 Anna M. Sokol A1 Jens Preussner A1 Stefan Guenther A1 Sawa Kostin A1 Clemens Ruppert A1 Aditya M. Bhagwat A1 Xuefei Ma A1 Johannes Graumann A1 Mario Looso A1 Andreas Guenther A1 Robert S. Adelstein A1 Stefan Offermanns A1 Didier Y.R. Stainier YR 2018 UL http://biorxiv.org/content/early/2018/09/11/414268.abstract AB 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 down-regulated 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.