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Nox2 redox signaling maintains essential cell populations in the brain

Nature Chemical Biology volume 7, pages 106–112 (2011)Cite this article

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Abstract

Reactive oxygen species (ROS) are conventionally classified as toxic consequences of aerobic life, and the brain is particularly susceptible to ROS-induced oxidative stress and damage owing to its high energy and oxygen demands. NADPH oxidases (Nox) are a widespread source of brain ROS implicated in seizures, stroke and neurodegeneration. A physiological role for ROS generation in normal brain function has not been established, despite the fact that mice and humans lacking functional Nox proteins have cognitive deficits. Using molecular imaging with Peroxyfluor-6 (PF6), a new selective fluorescent indicator for hydrogen peroxide (H2O2), we show that adult hippocampal stem/progenitor cells (AHPs) generate H2O2 through Nox2 to regulate intracellular growth signaling pathways, which in turn maintains their normal proliferation in vitro and in vivo. Our results challenge the traditional view that brain ROS are solely deleterious by demonstrating that controlled ROS chemistry is needed for maintaining specific cell populations.

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Figure 1: Spectroscopic characterization and cell culture validation of PF6-AM.
Figure 2: Application of PF6 to demonstrate that AHPs produce H2O2 upon FGF-2 stimulation.
Figure 3: Cellular redox status affects AHP growth signaling.
Figure 4: Nox2 is essential for normal proliferation of AHPs in vitro and in vivo.
Figure 5: Model for the role of Nox2 in FGF-2 redox signaling in AHPs.

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Acknowledgements

We thank the Packard and Sloan Foundations (C.J.C.), the UC Berkeley Hellman Faculty Fund (C.J.C.), Amgen, Astra Zeneca and Novartis (C.J.C.) and the US National Institutes of Health (GM 79465 to C.J.C. and EB 007295 to D.V.S.) for providing funding for this work. C.J.C. is an Investigator with the Howard Hughes Medical Institute. B.C.D. was partially supported by a Chemical Biology Training Grant from the US National Institutes of Health. (T32 GM066698). J.P. was partially supported by a training grant fellowship from the California Institute for Regenerative Medicine (T1-00007). We thank M. Quinn (Montana State University) for generous donation of Nox2 antibodies and T. Kawahara for helpful advice.

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Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, California, USA

    Bryan C Dickinson & Christopher J Chang

  2. Department of Chemical Engineering, University of California, Berkeley, California, USA

    Joseph Peltier, Daniel Stone & David V Schaffer

  3. Howard Hughes Medical Institute, University of California, Berkeley, California, USA

    Christopher J Chang

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  1. Bryan C Dickinson
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Contributions

B.C.D. synthesized all compounds in the paper and performed all analytical measurements, imaging assays and cell culture and mouse experiments. J.P. collaborated on cell culture, RT-PCR and mouse experiments. D.S. helped with mouse experiments. C.J.C., D.V.S., B.C.D. and J.P. designed experimental strategies. C.J.C. and B.C.D. wrote the paper with input from all coauthors.

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Correspondence to David V Schaffer or Christopher J Chang.

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Dickinson, B., Peltier, J., Stone, D. et al. Nox2 redox signaling maintains essential cell populations in the brain. Nat Chem Biol 7, 106–112 (2011). https://doi.org/10.1038/nchembio.497

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