Hypoxia-inducible factor 2α does not regulate cortical brain development

Dynamic changes in physiological oxygen levels are crucial for proper cortical brain development. In this context, oxygen is important not only for its role in energy metabolism but also as a signaling molecule. While much is already known about its most prominent signaling factor hypoxia-inducible factor (HIF)-1α, little is known about its functionally similar isoform HIF-2α during cortical development. Therefore, we utilized HIF-2α conditional knock-out mice (Emx1 and Nestin driven), which were kept under maternal hypoxia (10% pO2), physioxia (21% pO2), or hyperoxia (75% pO2) starting at E14.5 for 48 h and analyzed their cortical development by immunohistochemistry at E16.5. The analysis of newborn neurons (BrdU+) and cortical layer IV (Tbr1+), V (Ctip2+), and upper layer neurons (Satb2+) revealed clear effects of oxygen, with hyperoxia particularly increasing the number of Ctip2+/Tbr1- layer V neurons in E16.5 fetuses. However, neither the number of newborn neurons nor the number of layer-specific neurons was affected by HIF-2α CKO. Similarly, oxygen-related effects on neural stem cells (NSCs) and neuroprogenitor cells were not mediated by HIF-2α in E16.5 fetuses. Contributing, in vitro expansion and stem cell maintenance of NSCs were accelerated by physioxia (3% pO2) compared to hyperoxia (21% pO2), without involvement of HIF-2α under either condition. In conclusion, oxygen modulates cortical development, but HIF-2α does not mediate these effects. Thus, oxygen-related changes in neurogenesis and cortical morphology appear to be regulated via HIF-2α-independent mechanisms.