REST regulates the pool size of the different neural lineages by restricting the generation of neurons and oligodendrocytes from neural stem/progenitor cells

Abstract

2005; Westbrook et al., 2008). However, the function and significance of this differential regulation of REST during nervous system development and whether the normal low level of REST present in NS/P cells has any roles in maintaining NS/P cell self-renewal and/or differentiation along the different neural lineages remains largely unknown. SUMMARYREST is a master repressor of neuronal genes; however, whether it has any role during nervous system development remains largely unknown. Here, we analyzed systematically the role of REST in embryonic stem cells and multipotent neural stem/progenitor (NS/P) cells, including neurogenic and gliogenic NS/P cells derived from embryonic stem (ES) cells or developing mouse embryos. We showed that REST-null ES cells remained pluripotent and generated teratomas consisting of the three germ layers. By contrast, multipotent NS/P cells lacking REST displayed significantly reduced self-renewal capacity owing to reduced cell cycle kinetics and precocious neuronal differentiation. Importantly, although early-born neurogenic NS/P cells that lack REST were capable of differentiating to neurons and glia, the neuronal and oligodendrocytic pools were significantly enlarged and the astrocytic pool was shrunken. However, gliogenic NS/P cells lacking REST were able to generate a normal astrocytic pool size, suggesting that the shrinkage of the astrocytic pool generated from neurogenic NS/P cells lacking REST probably occurs by default. Microarray profiling of early-born NS/P cells lacking REST showed upregulation of neuronal as well as oligodendrocytic genes, specifically those involved in myelination. Furthermore, chromatin immunoprecipitation analyses showed that some of the upregulated oligodendrocytic genes contain an RE1 motif and are direct REST targets. Together, our data support a central role for REST during neural development in promoting NS/P cell self-renewal while restricting the generation and maturation of neurons and oligodendrocytes. KEY WORDS: Embryonic stem cells, Neural development, Neural stem/progenitor cells, Neurons, Oligodendrocytes, REST, MouseREST regulates the pool size of the different neural lineages by restricting the generation of neurons and oligodendrocytes from neural stem/progenitor cells

Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice

“…It is also a master regulator of neurogenesis and neurodevelopment, potentially as a hub for recruiting epigenetic chromatin-modifying enzymes, and may promote neural stem or progenitor cell self-renewal but restrict generation and maturation of neurons (for example, ref. 36), consistent with reduced maturation in the HD neural iPSCs. Additional targets of REST include GABA A receptor genes.…”

White spotting phenotype induced by targeted REST disruption during neural crest specification to a melanocyte cell lineage

“…Precocious neuronal differentiation and increase of oligodendrocytic differentiation of neural stem/progenitor cells lacking Rest expression (Covey et al . ) is seemingly in accordance with this notion. The growth and/or migratory potentials of the very early melanocyte precursors (the stage earlier than Dct or Tyr promoters start to work) could be promoted by Rest, and this may induce the white spotting phenotype in these mice.…”

Decoding transcriptional repressor complexes in the adult central nervous system

“…In pluripotent stem cells and neural progenitors, REST has been reported to orchestrate a network of genes related to neural development during embryonic and adult neurogenesis (Aoki et al, 2012; Ballas et al, 2005; Covey et al, 2012; Yamada et al, 2010). In undifferentiated neurons, REST expression declines as these cells mature during brain development.…”