Sirt1 contributes critically to the redox-dependent fate of neural progenitors.
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.
Prozorovski
Timour
T
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.
Schulze-Topphoff
Ulf
U
Glumm
Robert
R
Baumgart
Jan
J
Schröter
Friederike
F
Ninnemann
Olaf
O
Siegert
Elise
E
Bendix
Ivo
I
Brüstle
Oliver
O
Nitsch
Robert
R
Zipp
Frauke
F
Aktas
Orhan
O
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010084:Oxidation-Reduction; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D056970:Co-Repressor Proteins; D006657:Histones; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D056564:Sirtuin 1; D037761:Sirtuins; D000072056:Transcription Factor HES-1; C499317:Ascl1 protein, mouse; C489734:Hes1 protein, mouse; C434946:Tle1 protein, mouse; C470545:Sirt1 protein, mouse