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Nat Commun. 2015 May 13;6:7066. doi: 10.1038/ncomms8066.

Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2.

Author information

1
Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
2
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4SB, UK.
3
Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
4
Biogen Idec, 14 Cambridge Center, Cambridge, Massachusetts 02142, USA.

Abstract

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.

PMID:
25967870
PMCID:
PMC4441249
DOI:
10.1038/ncomms8066
[Indexed for MEDLINE]
Free PMC Article

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