Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells
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Chromatin modification plays a key role in fate decision of neural stem cells. Here, we explored the impact of epigenetic remodelling onto neuronal fate determination using specific inhibitors of histone deacetylases (iHDAC). Adult subventricular zone (SVZ) precursor cells were expanded as neurospheres and treated in vitro with second generation iHDAC MS-275, M344 and suberoylanilide hydroxamic acid (SAHA). All tested compounds revealed a significant increase of βIII-tubulin positive neurons (ranging from 258 to 431%) in a concentration-dependent manner. The number of oligodendrocytes was decreased by almost 50%, accompanied by a reduction of Olig2 mRNA expression. In contrast, astrocyte quantity remained unaffected after iHDAC treatment. Both control and iHDAC treated cells expressed markers of mature GABAergic and dopaminergic neurons. Increased expression levels of NeuroD, Cyclin D2 and B-lymphocyte translocation gene 3 (Btg3) point to a shift towards neuronal fate determination targeted by HDAC inhibitors.
KeywordsNeurospheres HDAC Adult stem cells Differentiation Acetylation
The authors thank D. Müller for excellent technical assistance. This work has been supported by the Bavarian Research Council (Munich) and the Johannes and Frieda Marohn Foundation (University of Erlangen). FAS is a fellow of the Studienstiftung des deutschen Volkes e.V. (German national merit foundation).
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