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Blood, 1 July 2006, Vol. 108, No. 1, pp. 134-140. Prepublished online as a Blood First Edition Paper on March 7, 2006; DOI 10.1182/blood-2005-03-1219. This Article Full Text (PDF) All Versions of this Article: 2005-03-1219v1 108/1/134    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 Sabri, S. Articles by Vainchenker, W. Search for Related Content PubMed PubMed Citation Articles by Sabri, S. Articles by Vainchenker, W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 25, 2005 Accepted February 16, 2006 Deficiency in the Wiskott Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment Siham Sabri, Adlen Foudi, Siham Boukour, Brigitte Franc, Sabine Charrier, Martine Jandrot-Perrus, Richard W Farndale, Abdelali Jalil, Mike P Blundell, Elisabeth M Cramer, Fawzia Louache, Najet Debili, Adrian J Thrasher, and William Vainchenker* INSERM U790, Universite Paris XI, Institut Gustave Roussy, Villejuif, France Departement d'Hematologie, INSERM U567, Institut Cochin, Maternite Port Royal, Paris, France Departement de Pathology, A. Pare Hospital (APHP), Universite de Versailles, Saint Quentin en Yvelines, France INSERM E348, Faculte Xavier Bichat, Paris, France Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom IFR54, Universite Paris XI, Institut Gustave Roussy, Villejuif, France Molecular Immunology Unit, Institute of Child Health, University College London, London, United Kingdom * Corresponding author; email: verpre{at}igr.fr. The pathophysiology of microthrombocytopenia in the Wiskott-Aldrich syndrome (WAS), and its milder form, X-linked thrombocytopenia (XLT) is unclear. Although quantitative defects are correctable by splenectomy, residual platelet abnormalities are suggestive of intrinsic disturbances of production. In contrast to human patients, murine models of WASp-deficiency exhibit only mild thrombocytopenia, and platelets are of normal size. Here we have identified a critical role for WASp during murine platelet biogenesis. By electron microscopy WASp-deficient MKs appeared to have shed platelets ectopically within the bone marrow space. WASp-deficient megakaryocytes (MKs) also displayed defects in response to fibrillar collagen I (CI) in vitro, the major matrix component of bone. These included a loss of normal CI receptor (21 integrin)-mediated inhibition of proplatelet formation, a marked abrogation of SDF-1-induced chemotactic migration of CD41+ MKs adherent to CI, and an almost complete lack of actin-rich podosomes, normally induced by interaction between CI and its receptors GPVI or 21 integrin. These findings highlight the central and highly specialized role of WASp in MKs during platelet biogenesis, and may provide a mechanism for the mild thrombocytopenia observed in WASp-deficient mice. In addition, they suggest a novel explanation for some of the platelet abnormalities characteristic of patients with the WAS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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