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Blood, 1 July 2007, Vol. 110, No. 1, pp. 171-179. Prepublished online as a Blood First Edition Paper on March 28, 2007; DOI 10.1182/blood-2007-02-071589. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-02-071589v1 110/1/171    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 Chen, Z. Articles by Shivdasani, R. A. Search for Related Content PubMed PubMed Citation Articles by Chen, Z. Articles by Shivdasani, R. A. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Cytoskeleton Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway Zhao Chen1,2, Olaia Naveiras3,4, Alessandra Balduini5, Akiko Mammoto6,7, Mary Anne Conti8, Robert S. Adelstein8, Donald Ingber6,7, George Q. Daley3,4, and Ramesh A. Shivdasani1,2 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2 Department of Medicine, Harvard Medical School, Boston, MA; 3 Division of Hematology and Oncology, Children's Hospital, Boston, MA; 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; 5 Department of Biochemistry, University of Pavia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy; 6 Vascular Biology Program, Children's Hospital, Boston, MA; 7 Departments of Pathology and Surgery, Harvard Medical School, Boston, MA; and 8 Laboratory of Molecular Cardiology, National Heart, Lung and Blood Institute, Bethesda, MD The gene implicated in the May-Hegglin anomaly and related macrothrombocytopenias, MYH9, encodes myosin-IIA, a protein that enables morphogenesis in diverse cell types. Defective myosin-IIA complexes are presumed to perturb megakaryocyte (MK) differentiation or generation of proplatelets. We observed that Myh9–/– mouse embryonic stem (ES) cells differentiate into MKs that are fully capable of proplatelet formation (PPF). In contrast, elevation of myosin-IIA activity, by exogenous expression or by mimicking constitutive phosphorylation of its regulatory myosin light chain (MLC), significantly attenuates PPF. This effect occurs only in the presence of myosin-IIA and implies that myosin-IIA influences thrombopoiesis negatively. MLC phosphorylation in MKs is regulated by Rho-associated kinase (ROCK), and consistent with our model, ROCK inhibition enhances PPF. Conversely, expression of AV14, a constitutive form of the ROCK activator Rho, blocks PPF, and this effect is rescued by simultaneous expression of a dominant inhibitory MLC form. Hematopoietic transplantation studies in mice confirm that interference with the putative Rho–ROCK–myosin-IIA pathway selectively decreases the number of circulating platelets. Our studies unveil a key regulatory pathway for platelet biogenesis and hint at Sdf-1/CXCL12 as one possible extracellular mediator. The unexpected mechanism for Myh9-associated thrombocytopenia may lead to new molecular approaches to manipulate thrombopoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: ROCK and Rho(ll) in bone marrow Alan T. Nurden Blood 2007 110: 5-6. [Full Text] [PDF] This article has been cited by other articles: A. E. Geddis The regulation of proplatelet production Haematologica, June 1, 2009; 94(6): 756 - 759. [Full Text] [PDF] A. Eckly, C. Strassel, M. Freund, J.-P. Cazenave, F. Lanza, C. Gachet, and C. Leon Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation Blood, April 2, 2009; 113(14): 3182 - 3189. [Abstract] [Full Text] [PDF] A. T. Nurden Thrombus stability on the vessel wall Blood, July 1, 2008; 112(1): 4 - 5. [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] N. A. Morin, P. W. Oakes, Y.-M. Hyun, D. Lee, Y. E. Chin, M. R. King, T. A. Springer, M. Shimaoka, J. X. Tang, J. S. Reichner, et al. Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration J. Exp. Med., January 21, 2008; 205(1): 195 - 205. [Abstract] [Full Text] [PDF] A. T. Nurden and P. Nurden Inherited thrombocytopenias Haematologica, September 1, 2007; 92(9): 1158 - 1164. 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