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

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Item Type:	Article
Title:	Sirt1 contributes critically to the redox-dependent fate of neural progenitors
Creators Name:	Prozorovski, T., Schulze-Topphoff, U., Glumm, R., Baumgart, J., Schroeter, F., Ninnemann, O., Siegert, E., Bendix, I., Bruestle, O., Nitsch, R., Zipp, F. and Aktas, O.
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.
Keywords:	Astrocytes, Basic Helix-Loop-Helix Transcription Factors, Brain, Cell Differentiation, Cell Lineage, Cultured Cells, Experimental Autoimmune Encephalomyelitis, Developmental Gene Expression Regulation, Histones, Homeodomain Proteins, Morphogenesis, Neurons, Oxidation-Reduction, Pregnancy, Promoter Regions, Small Interfering RNA, Repressor Proteins, Sirtuins, Stem Cells, Genetic Transcription, Animals, Mice
Source:	Nature Cell Biology
ISSN:	1465-7392
Publisher:	Nature Publishing Group
Volume:	10
Number:	4
Page Range:	385-394
Date:	April 2008
Official Publication:	https://doi.org/10.1038/ncb1700
PubMed:	View item in PubMed

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