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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3183-3191.
Prepublished online as a Blood First Edition Paper on July 30, 2007; DOI 10.1182/blood-2007-03-080184.
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Submitted March 15, 2007
Accepted July 20, 2007
Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion
Catherine Leon*, Anita Eckly, Beatrice Hechler, Boris Aleil, Monique Freund, Catherine Ravanat, Marie Jourdain, Christelle Nonne, Josiane Weber, Ralph Tiedt, Marie-Pierre Gratacap, Sonia Severin, Jean-Pierre Cazenave, Francois Lanza, Radek Skoda, and Christian Gachet
INSERM U.311, EFS-Alsace, Universite Louis Pasteur, Strasbourg, France
Department of Research, Experimental Hematology, Basel University Hospital, Basel, Switzerland
INSERM U563, Dentre de Physiopathologie de Toulouse, Dept d'Oncogenese et Signalisation dans les Cellules Hematopoietiques, U. Toulouse III Paul Sabatier, Toulouse, France
* Corresponding author; email: catherine.leon{at}efs-alsace.fr.
Mutations in the MYH9 gene encoding the non-muscle myosin heavy chain-IIA result in bleeding disorders characterized by a macrothrombocytopenia. To understand the role of myosin in normal platelet functions and in pathology, we generated mice with disruption of MYH9 in megakaryocytes. MYH9 mice displayed macrothrombocytopenia with a strong increase in bleeding time and absence of clot retraction. However, platelet aggregation and secretion in response to any agonist were near normal despite absence of initial platelet contraction. By contrast, integrin outside-in signaling was impaired, as observed by a decrease in integrin  3 phosphorylation and PtdIns(3,4)P2 accumulation following stimulation. Upon adhesion on a fibrinogen-coated surface, MYH9 platelets were still able to extend lamellipodia but without stress fiber-like formation. As a consequence, thrombus growth and organization, investigated under flow by perfusing whole blood over collagen, were strongly impaired. Thrombus stability was also decreased in vivo in a model of FeCl3-induced injury of carotid arteries. Overall, these results demonstrate that while myosin seems dispensable for aggregation and secretion in suspension, it plays a key role in platelet contractile phenomena and outside-in signaling. These roles of myosin in platelet functions, in addition to thrombocytopenia, account for the strong hemostatic defects observed in MYH9 mice.
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