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

doi:10.1038/ncomms8066

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

Centre for Oral, Clinical & Translational Sciences

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139 Citations (Scopus)

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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 language	English
Pages (from-to)	7066
Number of pages	1
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8066
Publication status	Published - 13 May 2015

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Neuronal development is promoted_BELL_Published2015_GOLD VoR (CC BY)Final published version, 2.27 MBLicence: CC BY

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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

@article{279665f4cb2549f28e66b26382b95fbb,

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

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.",

author = "Bell, {Karen F S} and Bashayer Al-Mubarak and Marc-Andr{\'e} Martel and Sean McKay and Nicola Wheelan and Philip Hasel and M{\'a}rkus, {N{\'o}ra M} and Paul Baxter and Deighton, {Ruth F} and Andrea Serio and Bilada Bilican and Sudhir Chowdhry and Meakin, {Paul J} and Ashford, {Michael L J} and Wyllie, {David J A} and Scannevin, {Robert H} and Siddharthan Chandran and Hayes, {John D} and Hardingham, {Giles E}",

year = "2015",

month = may,

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doi = "10.1038/ncomms8066",

language = "English",

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journal = "Nature Communications",

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Bell, KFS, Al-Mubarak, B, Martel, M-A, McKay, S, Wheelan, N, Hasel, P, Márkus, NM, Baxter, P, Deighton, RF, Serio, A, Bilican, B, Chowdhry, S, Meakin, PJ, Ashford, MLJ, Wyllie, DJA, Scannevin, RH, Chandran, S, Hayes, JD & Hardingham, GE 2015, 'Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2.', Nature Communications, vol. 6, pp. 7066. https://doi.org/10.1038/ncomms8066

TY - JOUR

T1 - Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2.

AU - Bell, Karen F S

AU - Al-Mubarak, Bashayer

AU - Martel, Marc-André

AU - McKay, Sean

AU - Wheelan, Nicola

AU - Hasel, Philip

AU - Márkus, Nóra M

AU - Baxter, Paul

AU - Deighton, Ruth F

AU - Serio, Andrea

AU - Bilican, Bilada

AU - Chowdhry, Sudhir

AU - Meakin, Paul J

AU - Ashford, Michael L J

AU - Wyllie, David J A

AU - Scannevin, Robert H

AU - Chandran, Siddharthan

AU - Hayes, John D

AU - Hardingham, Giles E

PY - 2015/5/13

Y1 - 2015/5/13

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms8066

DO - 10.1038/ncomms8066

M3 - Article

SN - 2041-1723

VL - 6

SP - 7066

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

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