Differential effects of RASA3 mutations on hematopoiesis are profoundly influenced by genetic background and molecular variant

Abstract

Studies of the severely pancytopenic scat mouse model first demonstrated the crucial role of RASA3, a dual RAS and RAP GTPase activating protein (GAP), in hematopoiesis. RASA3 is required for survival in utero; germline deletion is lethal at E12.5–13.5 due to severe hemorrhage. Here, conditional deletion in hematopoietic stem and progenitor cells (HSPCs) using Vav-iCre recapitulates the null phenotype demonstrating that RASA3 is required at the stem and progenitor level to maintain blood vessel development and integrity and effective blood production. In adults, bone marrow blood cell production and spleen stress erythropoiesis are suppressed significantly upon induction of RASA3 deficiency, leading to pancytopenia and death within two weeks. Notably, RASA3 missense mutations in two mouse models, scat (G125V) and hlb381 (H794L), show dramatically different hematopoietic consequences specific to both genetic background and molecular variant. The mutation effect is mediated at least in part by differential effects on RAS and RAP activation. In addition, we show that the role of RASA3 is conserved during human terminal erythropoiesis, highlighting a potential function for the RASA3-RAS axis in disordered erythropoiesis in humans. Finally, global transcriptomic studies in scat suggest potential targets to ameliorate disease progression.

RASA3 is a candidate gene in sickle cell disease‐associated pulmonary hypertension and pulmonary arterial hypertension

“…RASA3 plays a major role in erythropoiesis and thrombopoiesis through its interactions with Ras, regulating proliferation, survival, differentiation and actin skeleton organization. 40 , 41 , 42 , 43 , 44 RASA3 also mediates platelet signaling via Rap1. 17 Recently, RASA3 was identified as an important regulator of endothelial cell adhesion, permeability, and vascular lumen formation through its interactions with Rap1.…”

“…RASA3 is a GTPase activating protein responsible for repressing Rap1 and Ras activity. RASA3 plays a major role in erythropoiesis and thrombopoiesis through its interactions with Ras, regulating proliferation, survival, differentiation and actin skeleton organization 40–44 . RASA3 also mediates platelet signaling via Rap1 17 .…”