Acute postnatal ablation of Hif-2 results in anemia

Adaptive transcriptional responses to oxygen deprivation (hypoxia) are mediated by the hypoxia-inducible factors (HIFs), heterodimeric transcription factors composed of two basic helix–loop–helix–PAS family proteins. The transcriptional activity of HIF is determined by the hypoxic stabilization of the HIFproteins. HIF-1 and HIF-2 exhibit high sequence homology but have different mRNA expression patterns; HIF-1 is expressed ubiquitously whereas HIF-2 expression is more restricted to certain tissues, e.g., the endothelium, lung, brain, and neural crest derivatives. Germ-line deletion of either HIF subunit is embryonic lethal with unique features suggesting important roles for both HIFisoforms. Global deletion of Hif-2 results in distinct phenotypes depending on the mouse strain used for the mutation, clearly demonstrating an important role for HIF-2 in mouse development. The function of HIF-2 in adult life, however, remains incompletely understood. In this study, we describe the generation of a conditional murine Hif-2 allele and the effect of its acute postnatal ablation. Under very stringent conditions, we ablate Hif-2 after birth and compare the effect of acute global deletion of Hif-2 and Hif-1 . Our results demonstrate that HIF-2 plays a critical role in adult erythropoiesis, with acute deletion leading to anemia. Furthermore, although HIF-1 was first purified and cloned based on its affinity for the human erythropoietin (EPO) 3 enhancer hypoxia response element (HRE) and regulates Epo expression during mouse embryogenesis, HIF-2 is the critical isoform regulating Epo under physiologic and stress conditions in adults.