Rb Intrinsically Promotes Erythropoiesis by Coupling Cell Cycle Exit with Mitochondrial Biogenesis.

Regulation of the cell cycle is intimately linked to erythroid differentiation, yet how these processes are coupled at the molecular level is not well understood. In order to gain insight into this coordinate regulation, we examined the role that the retinoblastoma gene product (Rb), a central regulator of the cell cycle, plays in erythropoiesis. A conditional (floxed) Rb gene was specifically deleted in the erythroid compartment by means of EpoR-GFPcre, or in other hematopoietic compartments (with LysM-Cre and Mx1-Cre) in mice. We found that Rb serves a cell-type intrinsic and autonomous role in erythropoiesis. Deletion of Rb in the erythroid compartment results in an anemia due to ineffective erythropoiesis. A partial block in differentiation occurs at the transition from early to late erythroblasts. Unexpectedly, we found that in addition to a failure to properly exit the cell cycle, mitochondrial biogenesis fails to be upregulated at this transition point. The disturbance in mitochondrial activities was established through gene expression analysis, measures of respiratory function, as well as measurements of mtDNA content in sorted cell populations. The failure to upregulate mitochondrial biogenesis appears to contribute to the block in differentiation. The link between erythroid differentiation and mitochondrial function was validated by chemical inhibition of mitochondrial biogenesis and knockdown of the mitochondrial transcriptional coactivator PGC-1beta in cultured erythroid cells. The ineffective erythropoiesis seen in erythroid cells lacking Rb closely resembles the features of the refractory anemia seen in the context of the myelodysplastic syndromes (MDS). Prior work has demonstrated the presence of defects in cell cycle regulation as well as mitochondrial function in MDS. Our work demonstrates how these seemingly disparate pathways may play a role in coordinately regulating cellular differentiation.