Mice deficient for PHD2 and PHD3 display erythrocytosis and die prematurely. (A) cKO P2/P3 mice show enhanced HCTs compared with their WT littermates (n = 5). (B) WT, PHD3^−/− and cKO P2/P3 mice were followed for 20 weeks. cKO P2/P3 mice began to die shortly after birth (n = 7). (C) Expression profile (qRT-PCR) of different genes in the lysate of the entire brain of cKO P2 and cKO P2/P3 mice in relation to their respective WT littermates. *P < .05 is significantly different from cKO P2 samples (expression relative to their WT littermates; n = 5-7). (D) Schematic overview of the different genetic mouse models that were generated in this study showing nonlethal erythrocytotic cKO P2 mice that display a perfect balance between the protective HIF-1α activity and detrimental HIF-2α activity in the brain. In cKO P2/H1 mice, this balance is disturbed in favor of the HIF-2α activity leading to early lethality in the mice. All data are mean ± SEM (*P < .05, **P < .01).