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Sirt1 contributes critically to the redox-dependent fate of neural progenitors

Abstract

Repair processes that are activated in response to neuronal injury, be it inflammatory, ischaemic, metabolic, traumatic or other cause, are characterized by a failure to replenish neurons and by astrogliosis. The underlying molecular pathways, however, are poorly understood. Here, we show that subtle alterations of the redox state, found in different brain pathologies, regulate the fate of mouse neural progenitor cells (NPCs) through the histone deacetylase (HDAC) Sirt1. Mild oxidation or direct activation of Sirt1 suppressed proliferation of NPCs and directed their differentiation towards the astroglial lineage at the expense of the neuronal lineage, whereas reducing conditions had the opposite effect. Under oxidative conditions in vitro and in vivo, Sirt1 was upregulated in NPCs, bound to the transcription factor Hes1 and subsequently inhibited pro-neuronal Mash1. In utero shRNA-mediated knockdown of Sirt1 in NPCs prevented oxidation-mediated suppression of neurogenesis and caused upregulation of Mash1 in vivo. Our results provide evidence for an as yet unknown metabolic master switch that determines the fate of neural progenitors.

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Figure 1: Impact of redox and Sirt1 modulation on self-renewal and multipotentiality of NPCs.
Figure 2: Induction of Sirt1–Hes1 complex under oxidative conditions and effects of Sirt1 on Mash1 expression.
Figure 3: Mash1 promoter and expression analysis.
Figure 4: Low number of Sirt1(+)/Mash1(+) dual positive cells in the postnatal SVZ and RMS.
Figure 5: Induction of Sirt1 and inhibition of early NPCs in vivo.
Figure 6: Sirt1 expression patterns and modulation in experimental autoimmune encephalomyelitis (EAE).

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Acknowledgements

We thank Nancy Nowakowski and Sophia Bardehle for technical assistance, Alistair Noon and Andrew Mason for reading the manuscript as native English speakers and Christine Kutschbach for editorial assistance. We thank Frederick W. Alt and Yuko Fujiwara (Children's Hospital, Harvard Medical School and Howard Hughes Medical Institute, Boston) for providing Sirt1−/− mouse mating pairs, and Atugen AG (Berlin, Germany) for providing transfection lipids. This work was supported by grants from the Institute for Multiple Sclerosis Research Göttingen and the Gemeinnützige Hertie-Stiftung (to F. Z. and O. B.), the Deutsche Forschungsgemeinschaft (SFB-TRR 43 to R. N., F. Z. and O. A., as well as SFB 665 to R.N. and SFB 650 to F. Z.) and the Bundesministerium fr Bildung und Forschung (to F.Z.).

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Contributions

T. P., U. S.-T. and O. A. conceived and designed the initial study; O. B., R. N. and F. Z designed further experiments; T. P., U. S.-T., R. G., I. B., O. N., J. B., F. S. and E. S. performed the experiments; T. P., U. S.-T., R. G., F. S., O. B., R. N., F. Z. and O. A. analysed the data; O. A. wrote the manuscript with T. P. and F. Z.; F. Z. and O. A. edited the manuscript.

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Correspondence to Frauke Zipp.

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Supplementary Information

Supplementary Figures S1, S2, S3, S4, S5, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 977 kb)

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Prozorovski, T., Schulze-Topphoff, U., Glumm, R. et al. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 10, 385–394 (2008). https://doi.org/10.1038/ncb1700

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