Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2
Open accessAbstract
Forebrain neurons have weak intrinsic antioxidant defences compared with astrocytes, but the molecular basis and purpose of this is poorly understood. We show that early in mouse cortical neuronal development in vitro and in vivo , expression of the master-regulator of antioxidant genes, transcription factor NF-E2-related-factor-2 (Nrf2), is repressed by epigenetic inactivation of its promoter. Consequently, in contrast to astrocytes or young neurons, maturing neurons possess negligible Nrf2-dependent antioxidant defences, and exhibit no transcriptional responses to Nrf2 activators, or to ablation of Nrf2’s inhibitor Keap1. Neuronal Nrf2 inactivation seems to be required for proper development: in maturing neurons, ectopic Nrf2 expression inhibits neurite outgrowth and aborization, and electrophysiological maturation, including synaptogenesis. These defects arise because Nrf2 activity buffers neuronal redox status, inhibiting maturation processes dependent on redox-sensitive JNK and Wnt pathways. Thus, developmental epigenetic Nrf2 repression weakens neuronal antioxidant defences but is necessary to create an environment that supports neuronal development.
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Persistent activation of astrocytic NMDARs can activate NFE2L2-dependent gene expression, raising the possibility that synaptic activity can control the NFE2L2 pathway in astrocytes.
“Moreover, a recent study has shown that persistent activation of astrocytic NMDARs can activate NFE2L2-dependent gene expression, raising the possibility that synaptic activity can control the NFE2L2 pathway in astrocytes 83 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [83]
NFE2L2 is epigenetically repressed in cortical neurons early in development and what little NFE2L2 exists is highly unstable, leading to reduced intrinsic antioxidant defences.
“NFE2L2 is epigenetically repressed in cortical neurons early in development and what little NFE2L2 exists is highly unstable, leading to reduced intrinsic antioxidant defences 81,83 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [83]
NFE2L2 is only weakly activatable in neurons.
“NFE2L2 is only weakly activatable in neurons 81,83”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [83]
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- Authors
- Bell, K. F. S., Al-Mubarak, B., Martel, M.-A., McKay, S., Wheelan, N., Hasel, P., Márkus, N. M., Baxter, P., Deighton, R. F., Serio, A., Bilican, B., Chowdhry, S., Meakin, P. J., Ashford, M. L. J., Wyllie, D. J. A., Scannevin, R. H., Chandran, S., Hayes, J. D., & Hardingham, G. E.
- Affiliations
- University of Edinburgh (GB)
- MRC Centre for Regenerative Medicine (GB)
- University of Dundee (GB)
- Biogen (United States) (US)
- Corresponding author
- Hardingham, Giles E.
- ORCID
- Venue
- Nature Communications
- Published
- 2015-05-13
- Volume
- 6
- Issue
- 1
- Pages
- 7066-7066
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4441249
- OpenAlex
- W1823204572
- Cited by
- 191
- References
- 72
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 9 · 2023: 27 · 2022: 18 · 2021: 18 · 2020: 16 · 2019: 19 · 2018: 19 · 2017: 19 · 2016: 13 · 2015: 2
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Biogen
- Wellcome Trust
- Royal Society
- Diabetes UK (12/0004458)
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Nrf2, neuronal development, epigenetic repression, antioxidant defense, forebrain neurons, cortical neurons, Keap1, redox signaling, JNK signaling, Wnt signaling, synaptogenesis, neurite outgrowth, astrocytes, neuronal maturation
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Antioxidants, Cerebral Cortex, Cytoskeletal Proteins, Neurons, Mice, Knockout, Gene Expression Regulation, Developmental, Epigenesis, Genetic, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice, Electrophysiological Phenomena
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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