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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. This Article Full Text Full Text (PDF) Supplemental Methods, Figure, and Videos All Versions of this Article: blood-2007-03-080184v1 110/9/3183    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Léon, C. Articles by Gachet, C. Search for Related Content PubMed PubMed Citation Articles by Léon, C. Articles by Gachet, C. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Signal Transduction Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion Catherine Léon1,3, Anita Eckly1,3, Béatrice Hechler1,3, Boris Aleil1,3, Monique Freund1,3, Catherine Ravanat1,3, Marie Jourdain1,3, Christelle Nonne1,3, Josiane Weber1,3, Ralph Tiedt4, Marie-Pierre Gratacap5,6, Sonia Severin5,6, Jean-Pierre Cazenave1,3, François Lanza1,3, Radek Skoda4, and Christian Gachet1,3 1 INSERM, U311 Strasbourg, France; 2 Établissement Français du Sang–Alsace, Strasbourg, UMR-S311 France; 3 Université Louis Pasteur, Strasbourg, UMR-S311 France; 4 Department of Research, Experimental Hematology, University Hospital Basel, Basel, Switzerland; 5 Institut National de la Santé et de la Recherche Médicale, U563 Centre de Physiopathologie de Toulouse, Département d'Oncogenèse et Signalisation dans les Cellules Hématopoïétiques, Toulouse, France; 6 Université Toulouse III Paul Sabatier, Faculté de médecine Toulouse-Purpan, UMR-S563, Toulouse, France Mutations in the MYH9 gene encoding the nonmuscle 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 ß3 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: My, oh Myh9 ... and platelets, too Ramesh A. Shivdasani Blood 2007 110: 3093. [Full Text] [PDF] This article has been cited by other articles: J. M. Auger and S. P. Watson Dynamic Tyrosine Kinase-Regulated Signaling and Actin Polymerisation Mediate Aggregate Stability Under Shear Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1499 - 1504. [Abstract] [Full Text] [PDF] A. T. Nurden Thrombus stability on the vessel wall Blood, July 1, 2008; 112(1): 4 - 5. [Full Text] [PDF] A. Ono, E. Westein, S. Hsiao, W. S. Nesbitt, J. R. Hamilton, S. M. Schoenwaelder, and S. P. Jackson Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth Blood, July 1, 2008; 112(1): 90 - 99. [Abstract] [Full Text] [PDF] S. Kunishima, M. Hamaguchi, and H. Saito Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders Blood, March 15, 2008; 111(6): 3015 - 3023. [Abstract] [Full Text] [PDF]

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