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 geneticscreen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omicsanalyses and follow up studies, we find decreased Thrombospondinexpression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10expression is downregulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.