title: The scat mouse model highlights RASA3, a GTPase activating protein, as a key regulator of vertebrate erythropoiesis and megakaryopoiesis.
abstract: Although significant progress has been made in the past decades in our understanding of bone marrow failure syndromes and anemia, many pathological conditions of unknown origin remain. Mouse models have significantly contributed to our understanding of normal erythropoiesis and the pathogenesis of erythroid disorders. Recently, we identified in the scat (severe combined anemia and thrombocytopenia) mouse model a missense mutation (G125V) in the Rasa3 gene, encoding a Ras GTPase activating protein (GAP). RASA3 is lost during reticulocyte maturation through the exosomal pathway and is therefore absent in mature erythrocytes. In wild-type reticulocytes, RASA3 is bound to the plasma membrane, a prerequisite for its GAP activity, but is mislocalized to the cytosol in scat. This mislocalization leads to RASA3 loss of function and higher levels of Ras-GTP, the active form of Ras, are consistently found in scat mature red cells. Finally, RASA3 function is conserved among vertebrates, since erythropoiesis and thrombopoiesis are impaired in zebrafish in which rasa3 is knocked-down by morpholinos, and RASA3 is expressed in human erythroleukemia cells as well as in primary cells. In this commentary, we highlight the critical, conserved and non-redundant function of RASA3 in the context of vertebrate erythropoiesis and megakaryopoiesis. We notably discuss the mechanism of RASA3 downregulation and speculate on the most intriguing part of the phenotype observed in scat; the transient remission period.
authors.affiliation: The Jackson Laboratory; Bar Harbor, ME, USA.
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
authors.forename: Barry H
authors.initials: BH
authors.lastname: Paw
authors.forename: Lionel
authors.initials: L
authors.lastname: Blanc
mesh_terms: D000740:Anemia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D004920:Erythropoiesis; D020690:GTPase-Activating Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D013921:Thrombocytopenia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D034061:Thrombopoiesis
chemical_list: D020690:GTPase-Activating Proteins; C583390:RASA3 protein, mouse