IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms8066.html
   My bibliography  Save this article

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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Chowdh, 2015. "Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8066
    DOI: 10.1038/ncomms8066
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms8066
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms8066?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8066. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.