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Peer-reviewedCC BY 4.0PLOS One

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

  • Jennifer Lanto1
  • Laura Rohmann2
  • Tim Theege
  • Valeriia Abramenko
  • Lisa Große
  • Andreas Madlener
  • Julia Anna Elisabeth Neitzel
  • Alexander Storch
  • Franz Markert
  1. 1Department of Neurology, University of Rostock, Rostock, Mecklenburg-Western Pomerania, Germany
  2. 2German Centre for Neurodegenerative Diseases (DZNE) Rostock-Greifswald, Rostock, Mecklenburg-Western Pomerania, Germany
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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.

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Cite

BibTeXRIS
BibTeX
@article{lanto2026hypoxiainducible,
  title = {{Hypoxia-inducible factor 2α does not regulate cortical brain development}},
  author = {Jennifer Lanto and Laura Rohmann and Tim Theege and Valeriia Abramenko and Lisa Große and Andreas Madlener and Julia Anna Elisabeth Neitzel and Alexander Storch and Franz Markert},
  journal = {PLOS One},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pone.0359507},
  url = {https://doi.org/10.1371/journal.pone.0359507},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Hypoxia-inducible factor 2α does not regulate cortical brain development
AU  - Jennifer Lanto
AU  - Laura Rohmann
AU  - Tim Theege
AU  - Valeriia Abramenko
AU  - Lisa Große
AU  - Andreas Madlener
AU  - Julia Anna Elisabeth Neitzel
AU  - Alexander Storch
AU  - Franz Markert
PY  - 2026
DA  - 2026/10/14
JO  - PLOS One
DO  - 10.1371/journal.pone.0359507
UR  - https://doi.org/10.1371/journal.pone.0359507
AB  - 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.
SN  - 1932-6203
ER  -