Document Type

Article

Publication Date

12-28-2020

Keywords

JMG

JAX Source

PLoS Genet 2020 Dec 28; 16(12):e1008857

PMID

33370780

DOI

https://doi.org/10.1371/journal.pgen.1008857

Grant

HL134043

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.

Comments

We gratefully acknowledge the contribution the Genome Technologies, Flow Cytometry, Computational Sciences, and Histopathology Services at The Jackson Laboratory for expert assistance with the work described in this publication. We thank Dr. Mohandas Narla for the gift of the Band 3 antibody. This work is dedicated to the memory of Dr. Barry Paw, an outstanding scientist and wonderful colleague and friend who left us too soon. Dr Paw’s wisdom, advice, technical expertise, and helpful discussions were invaluable to our studies of RASA3.

This is an open access article distributed under the terms of the Creative Commons Attribution License.

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