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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytes / cytology
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Astrocytes / physiology
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Brain / cytology
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Brain / metabolism
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Brain / pathology
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Cell Differentiation / physiology*
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Cell Lineage
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Cells, Cultured
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Co-Repressor Proteins
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Gene Expression Regulation, Developmental
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Histones / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Morphogenesis / physiology
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Neurons / cytology
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Neurons / physiology*
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Oxidation-Reduction
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Pregnancy
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Promoter Regions, Genetic
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Sirtuin 1
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Sirtuins / genetics
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Sirtuins / metabolism*
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Stem Cells / cytology
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Stem Cells / physiology*
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Transcription Factor HES-1
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Transcription, Genetic
Substances
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Ascl1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Co-Repressor Proteins
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Hes1 protein, mouse
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Histones
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Homeodomain Proteins
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RNA, Small Interfering
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Repressor Proteins
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Tle1 protein, mouse
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Transcription Factor HES-1
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Sirt1 protein, mouse
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Sirtuin 1
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Sirtuins