Loss of α4A- and β1-tubulin leads to severe platelet spherocytosis and strongly impairs hemostasis in mice.
Fiche publication
Date publication
août 2022
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MANGIN Pierre
Tous les auteurs :
Kimmerlin Q, Moog S, Yakusheva AA, Eckly AE, Freund M, Závodszky G, Knapp Y, Mangin PH, Lanza F
Lien Pubmed
Résumé
Native circulating blood platelets present with a discoid flat morphology maintained by a sub-membranous peripheral ring of microtubules, named marginal band. The functional importance of this particular shape is still debated, but was initially hypothesized to facilitate platelet interaction with the injured vessel wall and to contribute to hemostasis. The importance of the platelet discoid morphology has since been questioned on the absence of clear bleeding tendency in mice lacking the platelet-specific b1 tubulin isotype, which exhibits platelets with a thinner marginal band and an ovoid shape. Here, we generated a mouse model inactivated for β1-tubulin and α4A-tubulin, an α-tubulin isotype strongly enriched in platelets. These mice present with fully spherical platelets completely devoid of a marginal band. In contrast to the single knockout, the double deletion resulted in a severe bleeding defect in a tail-clipping assay, which was not corrected by increasing the platelet count to normal values by the thrombopoietin-analog Romiplostim. In vivo, thrombus formation was almost abolished in a FeCl3-injury model, with only a thin layer of loosely packed platelets, and mice were protected against death in a model of thromboembolism. In vitro, platelets adhered less efficiently and formed smaller sized and loosely assembled aggregates when perfused over von Willebrand factor and collagen matrices. In conclusion, this study shows that blood platelets require two unique α- and β-tubulin isotypes to acquire their characteristic discoid morphology. Lack of these two isotypes has a deleterious effect on flow-dependent aggregate formation and stability, leading to a severe bleeding disorder.
Référence
Blood. 2022 08 26;: