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Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2002-03-0997. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-03-0997v1 100/6/2102    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 Kanaji, T. Articles by Ware, J. Search for Related Content PubMed PubMed Citation Articles by Kanaji, T. Articles by Ware, J. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2002, Vol. 100, No. 6, pp. 2102-2107 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome Taisuke Kanaji, Susan Russell, and Jerry Ware From the Roon Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA. An absent platelet glycoprotein (GP) Ib-IX receptor results in the Bernard-Soulier syndrome and is characterized by severe bleeding and the laboratory presentation of macrothrombocytopenia. Although the macrothrombocytopenic phenotype is directly linked to an absent GP Ib-IX complex, the disrupted molecular mechanisms that produce the macrothrombocytopenia are unknown. We have utilized a mouse model of the Bernard-Soulier syndrome to engineer platelets expressing an -subunit of GP Ib (GP Ib) in which most of the extracytoplasmic sequence has been replaced by an isolated domain of the -subunit of the human interleukin-4 receptor (IL-4R). The IL-4R/GP Ib fusion is membrane expressed in Chinese hamster ovary (CHO) cells, and its expression is facilitated by the presence of human GP IX and the -subunit of GP Ib. Transgenic animals expressing a chimeric receptor were generated and bred into the murine Bernard-Soulier syndrome-producing animals devoid of mouse GP Ib but expressing the IL-4R/GP Ib fusion sequence. The characterization of these mice revealed a 2-fold increase in circulating platelet count and a 50% reduction in platelet size when compared with platelets from the mouse model of the Bernard-Soulier syndrome. Immunoprecipitation confirmed that the IL-4R/GP Ib subunit interacts with filamin-1 and 14-3-3, known binding proteins to the GP Ib cytoplasmic tail. Mice expressing the chimeric receptor retain a severe bleeding phenotype, confirming a critical role for the GP Ib extracytoplasmic domain in hemostasis. These results provide in vivo insights into the structural elements of the GP Ib subunit that contribute to normal megakaryocyte maturation and thrombopoiesis. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Brill, A. K. Chauhan, M. Canault, M. T. Walsh, W. Bergmeier, and D. D. Wagner Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion Cardiovasc Res, October 1, 2009; 84(1): 137 - 144. [Abstract] [Full Text] [PDF] C. Dunois-Larde, C. Capron, S. Fichelson, T. Bauer, E. 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