Acute postnatal ablation of <i>Hif-2</i> α results in anemia

TLDR

Hypoxia‑inducible factors mediate transcriptional responses to low oxygen, with HIF‑1α ubiquitously expressed and HIF‑2α restricted to specific tissues; germ‑line deletion of either isoform is embryonic lethal, and the role of HIF‑2α in adult physiology remains unclear. The study aims to generate a conditional Hif‑2α allele and assess the effects of its acute postnatal deletion. The authors created a conditional Hif‑2α allele and acutely deleted it after birth, comparing the effects of global deletion of Hif‑2α versus Hif‑1α under stringent conditions. Acute postnatal deletion of Hif‑2α causes anemia and shows that HIF‑2α is essential for adult erythropoiesis, whereas HIF‑1α is not the primary regulator of erythropoietin in adult mice.

Abstract

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