Article abstract
Nature Cell Biology 10, 385 - 394 (2008)
Published online: 16 March 2008 | doi:10.1038/ncb1700
Sirt1 contributes critically to the redox-dependent fate of neural progenitors
Timour Prozorovski1,4, Ulf Schulze-Topphoff1,4, Robert Glumm1, Jan Baumgart2, Friederike Schröter1, Olaf Ninnemann2, Elise Siegert1, Ivo Bendix1, Oliver Brüstle3, Robert Nitsch2, Frauke Zipp1,4 & Orhan Aktas1,4
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.
- Cecilie Vogt Clinic for Neurology in the Helios Klinikum Berlin-Buch, Charité – Universitätsmedizin Berlin, and Max Delbrück Center for Molecular Medicine, Charitéplatz 1, 10117 Berlin, Germany.
- Institute for Cell and Neurobiology, Charité – Universitätsmedizin Berlin, Germany.
- Institute of Reconstructive Neurobiology, University of Bonn Medical Center and Hertie Foundation, 53105 Bonn, Germany.
- These authors contributed equally to this work.
Correspondence to: Frauke Zipp1,4 e-mail: frauke.zipp@charite.de