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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 1, 2007 Accepted March 21, 2007 The May-Hegglin anomaly gene Myh9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway Zhao Chen, Olaia Naveiras, Alessandra A Balduini, Akiko Mammoto, Mary Anne Conti, Robert S Adelstein, Donald Ingber, George Q Daley, and Ramesh A Shivdasani* Department of Medical Oncology, Dana-Farber Cancer Institute, and Dept of Medicine, Harvard Medical School, Boston, MA, United States Division of Hematology & Oncology, Children's Hospital, & Dept of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, United States Department of Biochemistry, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy Vascular Biology Program, Children's Hospital, & Depts of Pathology & Surgery, Harvard Medical School, Boston, MA, United States Laboratory of Molecular Cardiology, National Heart, Lung and Blood Institute, Bethesda, MD, United States * Corresponding author; email: ramesh_shivdasani{at}dfci.harvard.edu. 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 overexpression 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 RhoAv14, a constitutive form of the ROCK upstream activator Rho, blocks PPF, and this effect is rescued by simultaneous expression of a dominant inhibitory form of MLC. 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 point to Sdf-1/CXCL12 as one possible extra-cellular 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? 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