Journal Article

DZNE-2026-01068

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Hypoxia-inducible factor 2α does not regulate cortical brain development.

Lanto, J. ; Rohmann, L. ; Theege, T. ; Abramenko, V. ; Große, L. ; Madlener, A. ; Neitzel, J. A. E. ; Storch, A.DZNE* ; Markert, F.

2026
PLOS San Francisco, California, US

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Please use a persistent id in citations: doi:10.1371/journal.pone.0359507

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.

Keyword(s): Animals (MeSH) ; Basic Helix-Loop-Helix Proteins: metabolism (MeSH) ; Basic Helix-Loop-Helix Proteins: genetics (MeSH) ; Endothelial PAS Domain-Containing Protein 1 (MeSH) ; Mice (MeSH) ; Cerebral Cortex: embryology (MeSH) ; Cerebral Cortex: metabolism (MeSH) ; Cerebral Cortex: growth & development (MeSH) ; Mice, Knockout (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: cytology (MeSH) ; Neural Stem Cells: metabolism (MeSH) ; Neural Stem Cells: cytology (MeSH) ; Female (MeSH) ; Oxygen: metabolism (MeSH) ; Neurogenesis (MeSH) ; Neurodevelopment (MeSH) ; Basic Helix-Loop-Helix Proteins ; Endothelial PAS Domain-Containing Protein 1 ; Oxygen

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Contributing Institute(s):

1. Non-Motor Symptoms in Parkinson's disease (AG Storch)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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