Patricia Molina-Ortiz: Laboratory of Functional Genetics, GIGA-Research Centre, Université de Liège, Liège, and Welbio, Belgium.
Séléna Polizzi: Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM), Institut de Biologie et de Médecine Moléculaires (IBMM), Faculté de Médecine, Université Libre de Bruxelles, Gosselies, Belgium.
Eve Ramery: Laboratoire de Biologie Clinique, Faculté de Médecine-vétérinaire, Université de Liège, Liège, Belgium.
Stéphanie Gayral: Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM), Institut de Biologie et de Médecine Moléculaires (IBMM), Faculté de Médecine, Université Libre de Bruxelles, Gosselies, Belgium.
Céline Delierneux: Laboratory of Thrombosis and Hemostasis, GIGA-Research Centre, Université de Liège, Liège, Belgium.
Cécile Oury: Laboratory of Thrombosis and Hemostasis, GIGA-Research Centre, Université de Liège, Liège, Belgium.
Shintaro Iwashita: Mitsubishi Kagaku Institute of Life Sciences and Faculty of Pharmacy, Iwaki Meisei University, Iwaki, Japan.
Stéphane Schurmans: Laboratory of Functional Genetics, GIGA-Research Centre, Université de Liège, Liège, and Welbio, Belgium; Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM), Institut de Biologie et de Médecine Moléculaires (IBMM), Faculté de Médecine, Université Libre de Bruxelles, Gosselies, Belgium.
Rasa3 is a GTPase activating protein of the GAP1 family which targets Ras and Rap1. Ubiquitous Rasa3 catalytic inactivation in mouse results in early embryonic lethality. Here, we show that Rasa3 catalytic inactivation in mouse hematopoietic cells results in a lethal syndrome characterized by severe defects during megakaryopoiesis, thrombocytopenia and a predisposition to develop preleukemia. The main objective of this study was to define the cellular and the molecular mechanisms of terminal megakaryopoiesis alterations. We found that Rasa3 catalytic inactivation altered megakaryocyte development, adherence, migration, actin cytoskeleton organization and differentiation into proplatelet forming megakaryocytes. These megakaryocyte alterations were associated with an increased active Rap1 level and a constitutive integrin activation. Thus, these mice presented a severe thrombocytopenia, bleeding and anemia associated with an increased percentage of megakaryocytes in the bone marrow, bone marrow fibrosis, extramedular hematopoiesis, splenomegaly and premature death. Altogether, our results indicate that Rasa3 catalytic activity controls Rap1 activation and integrin signaling during megakaryocyte differentiation in mouse.
