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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 (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 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. Social Bookmarking                   What's this? Submitted April 1, 2002 Accepted May 9, 2002 Amelioration of the macrothrombocytopenia associated with the murine Bernard-Soulier syndrome Taisuke Kanaji, Susan Russell, and Jerry Ware* Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA * Corresponding author; email: jware{at}scripps.edu. 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engineer platelets expressing an -subunit of GP Ib (GP Ib) in which the majority of the extracytoplasmic sequence has been replaced by an isolated domain of the -subunit of the human interleukin 4 receptor (IL-4R).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 CHO cells and its expression is facilitated by the presence of human GP IX and the ß-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 two-fold increase in circulating platelet count and a 50% reduction in platelet size when compared to platelets from the mouse model of the Bernard-Soulier syndrome. Immunoprecipitation confirmed the IL-4R/GP Ib subunit interacts with filamin-1 and 14-3-3, known binding proteins to the GP Ibcytoplasmic tail. Mice expressing the chimeric receptor retain a severe bleeding phenotype, confirming a critical role for the GP Ib extracytoplasmic domain in hemostasis. 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