Work

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

Year: 2026

Type: article

Abstract: 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.

Source: PLoS ONE

DOI: 10.1371/journal.pone.0359507