title: Rasa3 controls megakaryocyte Rap1 activation, integrin signaling and differentiation into proplatelet.
abstract: 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.
authors: Laboratory of Functional Genetics, GIGA-Research Centre, Université de Liège, Liège, and Welbio, Belgium.
authors: Patricia
authors: P
authors: Molina-Ortiz
authors: 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.
authors: Séléna
authors: S
authors: Polizzi
authors: Laboratoire de Biologie Clinique, Faculté de Médecine-vétérinaire, Université de Liège, Liège, Belgium.
authors: Eve
authors: E
authors: Ramery
authors: 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.
authors: Stéphanie
authors: S
authors: Gayral
authors: Laboratory of Thrombosis and Hemostasis, GIGA-Research Centre, Université de Liège, Liège, Belgium.
authors: Céline
authors: C
authors: Delierneux
authors: Laboratory of Thrombosis and Hemostasis, GIGA-Research Centre, Université de Liège, Liège, Belgium.
authors: Cécile
authors: C
authors: Oury
authors: Mitsubishi Kagaku Institute of Life Sciences and Faculty of Pharmacy, Iwaki Meisei University, Iwaki, Japan.
authors: Shintaro
authors: S
authors: Iwashita
authors: 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.
authors: Stéphane
authors: S
authors: Schurmans
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D005269:Femur / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D016023:Integrins / Q000235:genetics; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000089804:Shelterin Complex; D015398:Signal Transduction / Q000235:genetics; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D016023:Integrins; C583390:RASA3 protein, mouse; D000089804:Shelterin Complex; C548558:TERF2IP protein, mouse; D034501:Telomere-Binding Proteins