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, Giles E. Hardingham (Lead / Corresponding author)

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    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.

    Original languageEnglish
    Article number7066
    Number of pages15
    JournalNature Communications
    Volume6
    DOIs
    Publication statusPublished - 13 May 2015

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    Hayes, John

    • Cellular Medicine - Professor (Teaching and Research) & Personal Chair of Molecular Carcinogenesis

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    Cite this

    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. (2015). Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2. Nature Communications, 6, [7066]. https://doi.org/10.1038/ncomms8066