[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Molina Ortiz, Patricia ; Université de Liège - ULiège > GIGA-R : Labo de génétique fonctionnelle
Polizzi, Séléna
Ramery, Eve ; Université de Liège - ULiège > Département de sciences fonctionnelles (DSF) > Biochimie
Gayral, Stéphanie
Delierneux, Céline ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine
Oury, Cécile ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine
Iwashita, Shintaro
Schurmans, Stéphane ; Université de Liège - ULiège > Département de sciences fonctionnelles (DSF) > Biochimie métabolique vétérinaire
Language :
English
Title :
Rasa3 Controls Megakaryocyte Rap1 Activation, Integrin Signaling and Differentiation into Proplatelet
Publication date :
2014
Journal title :
PLoS Genetics
ISSN :
1553-7390
eISSN :
1553-7404
Publisher :
Public Library of Science, San Francisco, United States - California
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