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

Karen F.S. Bell, Bashayer Al-Mubarak, Marc-André Martel, Sean McKay, Nicola Wheelan, Philip Hasel, Nóra M. Márkus, Paul Baxter, Ruth F. Deighton, Andrea Serio, Bilada Bilican, Sudhir Chowdhry, Paul J. Meakin, Michael L.J. Ashford, David J.A. Wyllie, Robert H. Scannevin, Siddharthan Chandran, John D. Hayes and Giles E. Hardingham ()
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Karen F.S. Bell: Centre for Integrative Physiology, University of Edinburgh
Bashayer Al-Mubarak: Centre for Integrative Physiology, University of Edinburgh
Marc-André Martel: Centre for Integrative Physiology, University of Edinburgh
Sean McKay: Centre for Integrative Physiology, University of Edinburgh
Nicola Wheelan: Centre for Integrative Physiology, University of Edinburgh
Philip Hasel: Centre for Integrative Physiology, University of Edinburgh
Nóra M. Márkus: Centre for Integrative Physiology, University of Edinburgh
Paul Baxter: Centre for Integrative Physiology, University of Edinburgh
Ruth F. Deighton: Centre for Integrative Physiology, University of Edinburgh
Andrea Serio: MRC Centre for Regenerative Medicine, University of Edinburgh
Bilada Bilican: MRC Centre for Regenerative Medicine, University of Edinburgh
Sudhir Chowdhry: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School
Paul J. Meakin: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School
Michael L.J. Ashford: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School
David J.A. Wyllie: Centre for Integrative Physiology, University of Edinburgh
Robert H. Scannevin: Biogen Idec, 14 Cambridge Center
Siddharthan Chandran: MRC Centre for Regenerative Medicine, University of Edinburgh
John D. Hayes: Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School
Giles E. Hardingham: Centre for Integrative Physiology, University of Edinburgh

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8066

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