Cyclin A2 regulates erythrocyte morphology and numbers

Abstract

Cyclin A2 is an essential gene for development and in haematopoietic stem cells and therefore its functions in definitive erythropoiesis have not been investigated. We have ablated cyclin A2 in committed erythroid progenitors in vivo using erythropoietin receptor promoter-driven Cre, which revealed its critical role in regulating erythrocyte morphology and numbers. Erythroid-specific cyclin A2 knockout mice are viable but displayed increased mean erythrocyte volume and reduced erythrocyte counts, as well as increased frequency of erythrocytes containing Howell-Jolly bodies. Erythroblasts lacking cyclin A2 displayed defective enucleation, resulting in reduced production of enucleated erythrocytes and increased frequencies of erythrocytes containing nuclear remnants. Deletion of the Cdk inhibitor p27 Kip1 but not Cdk2, ameliorated the erythroid defects resulting from deficiency of cyclin A2, confirming the critical role of cyclin A2/Cdk activity in erythroid development. Loss of cyclin A2 in bone marrow cells in semisolid culture prevented the formation of BFU-E but not CFU-E colonies, uncovering its essential role in BFU-E function. Our data unveils the critical functions of cyclin A2 in regulating mammalian erythropoiesis.

Orchestration of late events in erythropoiesis by KLF1/EKLF

“…Its more precise function in erythropoiesis was recently illuminated by conditional ablation studies [36*]. Deletion of the gene in the erythroid compartment led to a greater RDW, increased Howell-Jolly bodies, and deficiency in enucleation in spite of normal proliferation and differentiation.…”

How to expel a bad tenant: Linking cyclin A2, enucleation and cell size

“…2 Cyclin A2 is a key cell cycle regulator that through activation of its catalytic partners CDK2 and CDK1, is best known for its role in controlling the onset and completion of DNA replication in S-phase, as well as regulating G2-M progression. Cyclin A2 knockout mice are embryonically lethal, and its conditional depletion from the haematopoietic compartment results in pancytopenia as a result of a decrease in stem cell proliferation.…”

“…6 Here, Jayapal et al use powerful in vivo conditional mouse models to provide novel insight into the definitive role of cyclin A2 in erythropoiesis. 2 Using erythroid specific deletion of cyclin A2, the authors show that cyclin A2 controls red blood cell size (MCV) and numbers by regulating not only the formation of early erythroid progenitors (BFU-E; burstforming unit-erythroid colonies), but surprisingly by also acting at a later time point of erythroid development, enabling efficient nuclear extrusion in vitro and in vivo.…”

“…Indeed, DNA damage in erythroblasts was found to be more severe in the absence of cyclin A2, linking cyclin A2 to DNA damage repair. 2 In addition, as the authors note, impairing DNA synthesis and DNA damage checkpoints genes is already known to result in decreased red blood cell numbers and cell size leading to macrocytic anemia. Although the process of erythroid enucleation shares many similarities with an asymmetric cell division, there is no DNA synthesis step.…”

“…by sensing DNA damage/chromatin compaction. 2 Of interest, compound loss of p27 was shown to partially rescue the erythroid size and enucleation phenotype due to loss of Cyclin A2 indicating that as with other cell cycle functions, a balance of p27 and cyclin A2 is required to regulate erythropoiesis and enucleation. dynamic coordination of the cytoskeleton during enucleation.…”