Published online 18 April 2009
Haematologica, Vol 94, Issue 6, 800-810 doi:10.3324/haematol.2008.001032
Copyright © 2009 by Ferrata Storti Foundation
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Original Article

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Catherine Strassel, Anita Eckly, Catherine Léon, Claire Petitjean, Monique Freund, Jean-Pierre Cazenave, Christian Gachet, François Lanza

UMR-S949 INSERM, Université de Strasbourg, EFS-Alsace, Strasbourg, France

Correspondence: François Lanza, INSERM U949, EFS-Alsace, 10 rue Spielmann 67000 Strasbourg. E-mail:francois.lanza{at}efs-alsace.fr

Background: Giant platelets and thrombocytopenia are invariable defects in the Bernard-Soulier syndrome caused by deficiency of the GPIb-V-IX complex, a receptor for von Willebrand factor supporting platelet adhesion to the damaged arterial wall. Various properties of this receptor may be considered potential determinants of the macrothrombocytopenia.

Design and Methods: To explore the underlying mechanisms of the disease, megakaryopoiesis was studied in a mouse model deficient in GPIbβ. Megakaryocytes were initially characterized in situ in the bone marrow of adult mice, after which their capacity to differentiate into proplatelet-bearing cells was evaluated in cultured fetal liver cells.

Results: The number of megakaryocyte progenitors, their differentiation and progressive maturation into distinct classes and their level of endoreplication were normal in GPIbβ–/– bone marrow. However, the more mature cells exhibited ultrastructural anomalies with a thicker peripheral zone and a less well developed demarcation membrane system. GPIbβ–/– megakaryocytes could be differentiated in culture from Lin– fetal liver cells in normal amounts but the proportion of cells able to extend proplatelets was decreased by 41%. Moreover, the GPIbβ–/– cells extending proplatelets displayed an abnormal morphology characterized by fewer pseudopodial extensions with thicker shaft sections and an increased diameter of the terminal coiled elements. GPIbβ–/– released platelets were larger but retained a typical discoid shape. Proplatelet formation was similarly affected in bone marrow explants from adult mice examined by videomicroscopy. The marginal microtubular ring contained twice as many tubulin fibers in GPIbβ–/– proplatelet buds in cultured and circulating platelets.

Conclusions: Altogether, these findings point to a role of the GPIb-V-IX complex intrinsic to megakaryocytes at the stage of proplatelet formation and suggest a functional link with the underlying microtubular cytoskeleton in platelet biogenesis.

Key words: megakaryocyte, platelet, Bernar-Soulier, microtubules, GPIb-V-IX.


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