RT Journal Article
SR Electronic
T1 Requirement for Anti-Apoptotic MCL-1 during Early Erythropoiesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.06.081422
DO 10.1101/2020.05.06.081422
A1 Meghan E. Turnis
A1 Ewa Kaminska
A1 Kaitlyn H. Smith
A1 Brittany J. Kartchner
A1 Peter Vogel
A1 Jonathan D. Laxton
A1 Richard A. Ashmun
A1 Paul A. Ney
A1 Joseph T. Opferman
YR 2020
UL http://biorxiv.org/content/early/2020/05/08/2020.05.06.081422.abstract
AB Mature erythrocytes are under tight homeostatic control with the need for constant replacement from progenitors to replace damaged or obsolete red blood cells (RBCs). This process is regulated largely by erythropoietin (Epo) which promotes the survival of erythroid progenitors and facilitates their differentiation and proliferation. Ablation of Bcl2l1 (which encodes BCL-xL) results in embryonic lethality with a lack of mature erythrocytes but does not perturb erythroid progenitors. Similarly, conditional Bcl2l1-deletion results in severe anemia with the death of late erythroid progenitors and induction of extramedullary erythropoiesis. While BCL-xL is critical to the survival of mature erythrocytes, it is still unclear whether other anti-apoptotic molecules mediate survival during earlier stages of erythropoiesis. Here, we demonstrate that erythroid-specific Mcl1-deletion results in embryonic lethality due to severe anemia caused by a lack of mature RBCs. Mcl1-deleted embryos exhibit stunted growth, ischemic necrosis, and decreased RBCs in the blood. Furthermore, we demonstrate that the dependence on MCL-1 is only during early erythropoiesis, whereas during later stages the cells become MCL-1-independent and upregulate the expression of BCL-xL. Functionally, MCL-1 relies upon its ability to prevent apoptosis to promote erythroid development since co-deletion of the pro-apoptotic effectors Bax and Bak can overcome the requirement for MCL-1 expression. Furthermore, ectopic expression of human BCL2 in erythroid progenitors can compensate for Mcl1 deletion, indicating redundancy between these two anti-apoptotic family members. These data clearly demonstrate a requirement for MCL-1 in promoting survival of early erythroid progenitors.Competing Interest StatementThe authors have declared no competing interest.