Although neural progenitor cells (NPCs) can differentiate into neurons, astrocytes, or oligodendrocytes, brain injury typically stimulates production of astrocytes in preference to neurons (see Libert et al.). Noting that various neurological diseases are associated with inflammation, which promotes oxidative conditions, Prozorovski et al. investigated the effects of redox state on NPC differentiation. Pharmacological inhibition of antioxidative enzymes (oxidative conditions) decreased proliferation of mouse cortical NPCs cultured in the presence of basic fibroblast growth factor (bFGF), whereas reducing conditions enhanced NPC proliferation. The fraction of cells that differentiated into astrocytes after bFGF withdrawal was greater when NPCs had been cultured under oxidative conditions, whereas the fraction that differentiated into neurons was smaller. In contrast, cells that had been cultured under reducing conditions were more likely to differentiate into neurons and less likely to differentiate into astrocytes. Expression of the histone deacetylase Sirt1 was increased in NPCs cultured under oxidative conditions, and Sirt1 knockdown with siRNA blocked the effects of oxidation on NPC differentiation. Oxidative conditions promoted association of Sirt1 with the transcription factor Hes1 and with the promoter of Mash1, which encodes a neurogenic transcription factor, and led to decreased acetylation of histone H3, residue Lys9, and a Sirt1-dependent decrease in Mash1 expression. Mouse pups injected with a pro-oxidant showed an increase in Sirt1 immunoreactivity in a germinal region of the brain, along with a decrease in neurogenesis; in utero electroporation with shRNA directed against Sirt1 increased neurogenesis in such oxidant-treated pups. Thus, the authors conclude that nontoxic manipulation of redox conditions can influence NPC fate and that Sirt1 plays a critical role in this process.
T. Prozorovski, U. Schulze-Topphoff, R. Glumm, J. Baumgart, F. Schröter, O. Ninnemann, E. Siegert, I. Bendix, O. Brüstle, R. Nitsch, F. Zipp, O. Aktas, Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat. Cell Biol. 10, 385-394 (2008). [PubMed]
S. Libert, D. Cohen, L. Guarente, Neurogenesis directed by Sirt1. Nat. Cell Biol. 10, 373-374 (2008). [PubMed]