Cell fate: The path to neurogenesis

Abstract

mammalian brain are multipotent: they can differentiate into neurons, astrocytes or oligodendrocytes during development and in healthy adults. However, the factors that influence NPC differentiation remain poorly characterized. A new study shows that, in mice, the cellular redox state plays a part, through effects on the histone deacetylase (HDAC) Sirt1. NPC proliferation and differentiation following CNS damage can replenish lost cells and restore neural capacity. In many pathological conditions, however, particularly those in which inflammation is involved, astrocyte production dominates, resulting in a dearth of replacement neurons. The group of Zipp and Aktas investigated possible causes of this skew, which could potentially be manipulated in certain neurological disorders. As inflammation generates oxidative conditions, the authors first assessed in vitro whether the intracellular redox state of NPCs affects their proliferation. They found that, relative to control cultures, incubation with various pro-oxidative chemical species reduced the total number of NPCs and decreased the proportion of proliferating cells. Conversely, incubation with reducing species had the opposite effect. Thus, an oxidative environment might oppose neural regeneration. Next they set out to ascertain whether the cellular redox state also affects NPC differentiation, which can be prompted in culture by withdrawal of basic fibroblast growth factor (bFGF) from the culture medium. They found that incubation under oxidative conditions for 7 days following bFGF removal increased the proportion of astrocytes and decreased the proportion of neurons produced. By contrast, incubation under reducing conditions decreased the proportion of astrocytes while increasing the proportion of neurons. To determine the factors that mediate the effects of the oxidative environment on NPC differentiation, the authors looked at the expression levels of proteins that are known to be involved in this process. They found that, in differentiating NPCs, expression of the redox-sensitive HDAC Sirt1 was increased by oxidative incubation. In accordance, addition of the Sirt1 activator resveratrol to redox-normal NPC cultures two days prior to differentiation mimicked the effect of oxidative conditions, whereas small-interferingRNA (siRNA) knock-down of Sirt1 prior to oxidative challenge abrogated the effect. Follow-up immunoprecipitation experiments showed that oxidative conditions also increased Sirt1 binding to the transcription factor Hes1, a protein that is known to repress the expression of the pro-neuronal-fate transcription factor Mash1. Indeed, the authors then showed that both oxidising conditions and direct Sirt1 activation by resveratrol decreased Mash1 expression. Further investigation revealed that the oxidative challenge increased the binding of Sirt1–Hes1 to the Mash1-gene promoter region and thus increased deacetylation of this region, downregulating the gene’s transcription. Additional in vivo experiments showed that Mash1 and Sirt1 expression overlap very little in progenitors in the normal mouse brain, facilitating neurogenesis during development. Oxidative challenge increased Sirt1 expression and decreased Mash1 expression in NPCs, downregulating neurogenesis and thus replicating the outcome of the in vitro experiments. These findings show that, in mouse NPCs, an oxidative environment skews NPC differentiation in favour of astrogenesis, as a result of increased Sirt1and Hes1-mediated downregulation of the Mash1 gene. The results might contribute to the development of methods to stimulate neuronal differentiation of stem cells in patients with neurological disorders and CNS damage. Craig Nicholson

DOI: 10.1038/nrn2378

Cite this paper

@article{Nicholson2008CellFT, title={Cell fate: The path to neurogenesis}, author={Craig Nicholson}, journal={Nature Reviews Neuroscience}, year={2008}, volume={9}, pages={329-329} }