Sox6 is necessary for efficient erythropoiesis in adult mice under physiological and anemia-induced stress conditions

Abstract

Background: Definitive erythropoiesis is a vital process throughout life. Both its basal activity under physiological conditionsand its increased activity under anemia-induced stress conditions are highly stimulated by the hormone erythropoietin. Thetranscription factor Sox6 was previously shown to enhance fetal erythropoiesis together and beyond erythropoietinsignaling, but its importance in adulthood and mechanisms of action remain unknown. We used here Sox6 conditional nullmice and molecular assays to address these questions.Methodology/Principal Findings: Sox6fl/flErGFPCre adult mice, which lacked Sox6 in erythroid cells, exhibited compensatedanemia, erythroid cell developmental defects, and anisocytotic, short-lived red cells under physiological conditions, provingthat Sox6 promotes basal erythropoiesis. Tamoxifen treatment of Sox6fl/flCaggCreER mice induced widespread inactivationof Sox6 in a timely controlled manner and resulted in erythroblast defects before reticulocytosis, demonstrating thatimpaired erythropoiesis is a primary cause rather than consequence of anemia in the absence of Sox6. Twenty five percentof Sox6fl/flErGFPCre mice died 4 or 5 days after induction of acute anemia with phenylhydrazine. The others recovered slowly.They promptly increased their erythropoietin level and amplified their erythroid progenitor pool, but then exhibited severeerythroblast and reticulocyte defects. Sox6 is thus essential in the maturation phase of stress erythropoiesis that follows theerythropoietin-dependent amplification phase. Sox6 inactivation resulted in upregulation of embryonic globin genes, butembryonic globin chains remained scarce and apparently inconsequential. Sox6 inactivation also resulted in downregulationof erythroid terminal markers, including the Bcl2l1 gene for the anti-apoptotic factor Bcl-xL, and in vitro assays indicated thatSox6 directly upregulates Bcl2l1 downstream of and beyond erythropoietin signaling.Conclusions/Significance: This study demonstrates that Sox6 is necessary for efficient erythropoiesis in adult mice underboth basal and stress conditions. It is primarily involved in enhancing the survival rate and maturation process of erythroidcells and acts at least in part by upregulating Bcl2l1. © 2010 Dumitriu et al.