title: Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment.
abstract: 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 (alpha2beta1 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 alpha2beta1 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 WAS.
authors.affiliation: Institut National de la Santé etde la Recherche Médicale (INSERM), U790, Université Paris XI, Institut Gustave Roussy, Villejut, France. s.sabri@shaw.ca
authors.forename: Siham
authors.initials: S
authors.lastname: Sabri
authors.forename: Adlen
authors.initials: A
authors.lastname: Foudi
authors.forename: Siham
authors.initials: S
authors.lastname: Boukour
authors.forename: Brigitte
authors.initials: B
authors.lastname: Franc
authors.forename: Sabine
authors.initials: S
authors.lastname: Charrier
authors.forename: Martine
authors.initials: M
authors.lastname: Jandrot-Perrus
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
authors.forename: Abdelali
authors.initials: A
authors.lastname: Jalil
authors.forename: Mike P
authors.initials: MP
authors.lastname: Blundell
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Cramer
authors.forename: Fawzia
authors.initials: F
authors.lastname: Louache
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001853:Bone Marrow / Q000473:pathology* / Q000503:physiopathology*; D002454:Cell Differentiation / Q000235:genetics; D024042:Collagen Type I / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D038982:Integrin alpha2beta1 / Q000378:metabolism; D008533:Megakaryocytes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013921:Thrombocytopenia / Q000235:genetics / Q000473:pathology*; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000172:deficiency* / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D038982:Integrin alpha2beta1; C495772:Wasl protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal