Abstract
Multipotent neural stem cells (NSCs) possess the ability to self-renew and differentiate into both neurons and glia. However, the detailed mechanisms underlying NSC fate decisions are not well understood. Recent work suggests that the interaction between cell type specific transcription factors and microRNAs (miRNAs) is important as resident neural stem/progenitor cells give rise to functionally mature neurons. Recently, we demonstrated that the transcriptional repressor REST (RE1-silencing transcription factor) is essential to prevent precocious neuronal differentiation and maintain NSC self-renewal in the adult hippocampus. Here we show that REST is required for orchestrating the expression of distinct subsets of miRNAs in primary mouse NSC cultures, a physiologically relevant cell type. Using miRNA array profiling, we identified known REST-regulated miRNA genes, as well as previously uncharacterized REST-dependent miRNAs. Interestingly, in response to proliferation and differentiation stimuli, REST-regulated miRNAs formed distinct clusters and displayed variable expression dynamics. These results suggest that REST functions in a context-dependent manner through its target miRNAs for mediating neuronal production.
Highlights
The process of neuronal production from multipotent neural stem cells (NSCs) continues in the postnatal and adult mammalian brain in two discrete locations: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus (Ming and Song, 2005; Kempermann et al, 2008)
The transcriptional repressor REST has been the focus of research for many years, and is linked to neurological disorders such as Huntington’s disease and epilepsy (Zuccato et al, 2003; Jessberger et al, 2007)
We recently demonstrated that REST is required for the coordination of the neuronal gene program to ensure a balance between neuronal production and maintaining the NSC pool (Gao et al, 2011)
Summary
The process of neuronal production from multipotent neural stem cells (NSCs) continues in the postnatal and adult mammalian brain in two discrete locations: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus (Ming and Song, 2005; Kempermann et al, 2008). SGZ and SVZ neurogenesis is regulated by both extrinsic factors, such as receptor-mediated signaling pathways (Ming and Song, 2005), and intrinsic factors, such as epigenetic mechanisms (Hsieh and Gage, 2004). Epigenetic mechanisms, including histone modifications and chromatin remodeling, have emerged to play critical roles in NSC self-renewal and differentiation (Hsieh and Gage, 2004). Recent bioinformatics analyses reveal more than 1300 RE1 sites throughout the mammalian genome (Bruce et al, 2004; Johnson et al, 2007), consistent with the widespread role of REST
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