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.

Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation

“…Recently, Prozorovski et al (30) showed that oxidative conditions repressed Mash1 expression in neonates and cultured NPCs from E17.5 embryos and indicated that the repression of Mash1 was mediated by the complex of Hes1 and SIRT1. They suggested that SIRT1 participated in oxidation-mediated suppression of neurogenesis.…”

Sirtuin 1 regulation of developmental genes during differentiation of stem cells

“…SIRT1 was shown to regulate the promoter of the MashI gene in somatic stem cell neural differentiation in mice (5). To identify the downstream effects of SIRT1 down-regulation in hESC differentiation, we performed chromatin IP (ChIP) experiments in Shef-1 hESC by using an anti-SIRT1 antibody and by hybridizing the immunoprecipitated DNA fragments on an Agilent human promoter ChIP-on-chip microarray containing 474,392 probes, which cover almost all described human promoters and many known regulatory regions.…”

Epigenetic regulation of aging stem cells

“…Defects in HSC self-renewal under both basal and low oxygen conditions are exacerbated in older mice compared with young adults (Ou et al, 2010). The role of SIRT1 in adult NSCs has not yet been characterized, but SIRT1 plays a role in directing cell fate decisions of embryonic neural progenitors in response to different extracellular conditions (Hisahara et al, 2008;Prozorovski et al, 2008). In the presence of low amounts of growth factors, SIRT1 promotes neuronal differentiation in cultures of murine neural progenitors, and acute deletion of Sirt1 at embryonic stages results in fewer neurons in vivo (Hisahara et al, 2008).…”

“…In the presence of low amounts of growth factors, SIRT1 promotes neuronal differentiation in cultures of murine neural progenitors, and acute deletion of Sirt1 at embryonic stages results in fewer neurons in vivo (Hisahara et al, 2008). However, under conditions of mild oxidative stress, SIRT1 contributes to decreased production of neurons and increased astrocytes, an effect linked to SIRT1's effects on H3K9ac levels of proneural gene Mash1/Ascl1 (Prozorovski et al, 2008). In the context of increased oxidative stress in the brain during aging or disease (Monje et al, 2003), misregulation of SIRT1 may contribute to the decrease in neurogenesis with age.…”