Acute postnatal ablation of Hif-2α results in anemia

Adaptive transcriptional responses to oxygen deprivation (hypoxia) are mediated by the hypoxia-inducible factors (Hill's), 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 HIF-alpha proteins. HIF-1 alpha and HIF-2 alpha exhibit high sequence homology but have different mRNA expression patterns; HIF-1 alpha is expressed ubiquitously whereas HIF-2 alpha 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 HIF-alpha isoforms. Global deletion of Hif-2 alpha results in distinct phenotypes depending on the mouse strain used for the mutation, clearly demonstrating an important role for HIF-2 alpha in mouse development. The function of HIF-2 alpha in adult life, however, remains incompletely understood. In this study, we describe the generation of a conditional murine Hif-2 alpha allele and the effect of its acute postnatal ablation. Under very stringent conditions, we ablate Hif-2 alpha after birth and compare the effect of acute global deletion of Hif-2 alpha and Hif-l alpha. Our results demonstrate that HIF-2 alpha plays a critical role in adult erythropoiesis, with acute deletion leading to anemia. Furthermore, although HIF-1 alpha 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 alpha is the critical a isoform regulating Epo under physiologic and stress conditions in adults.