with megakaryocyte-restricted MYH9 inactivation Abnormal megakaryocyte morphology and proplatelet formation in mice

Abstract Mutations in the MYH9 gene encoding non-muscle myosinIIA lead to macrothrombocytopenia as observed in MYH9- related disorders. We used mice with megakaryocyte-restricted MYH9 inactivation to explore the role of myosinin thrombopoiesis. In situ, bone marrow MYH9 megakaryocyteswere irregularly shaped, appearing leaky with poorly defined limits. The demarcation membranes were abnormally organized and poorly developed, pointing to an insufficient reservoir for the future formation of platelets. The cytoskeletal-rich peripheral zone was lacking due to the absence of the myosinfilament network which normally surrounds the granular zone in wild-type cells. In vitro studies of cultured cells showed that MYH9 megakaryocyteswere unable to form stress fibersupon adhesion to collagen, suggesting that the leaky shape results from defects in internal tension and anchorage to the extracellular environment. Surprisingly, the proportion of cells extending proplatelets was increased in MYH9