Repressor element 1 silencing transcription factor (REST) controls radial migration and temporal neuronal specification during neocortical development

Abstract

Neurogenesis requires mechanisms that coordinate early cell-fate decisions, migration, and terminal differentiation. Here, we show that the transcriptional repressor, repressor element 1 silencing transcription factor (REST), regulates radial migration and the timing of neural progenitor differentiation during neocortical development, and that the regulation is contingent upon differential REST levels. Specifically, a sustained presence of REST blocks migration and greatly delays-but does not prevent-neuronal differentiation, resulting in a subcortical band heterotopia-like phenotype, reminiscent of loss of doublecortin. We further show that doublecortin is a direct gene target of REST, and that its overexpression rescues, at least in part, the aberrant phenotype caused by persistent presence of REST. Our studies support the view that the targeted down-regulation of REST to low levels in neural progenitors, and its subsequent disappearance during neurogenesis, is critical for timing the spatiotemporal transition of neural progenitor cells to neurons.in utero electroporation | neuronal differentiation | neuronal cell fate N ervous system development relies on extrinsic and intrinsic signaling to regulate the precise spatial and temporal acquisition of the different neural lineages. Neurons and glia arise from neural stem cells in a temporally defined order, where generation of neurons precedes glia (1-3). Furthermore, the generation and migration of neurons occur in a stereotyped pattern to construct the distinctive structure of the central nervous system. For example, the neocortex, which consists of six layers of neurons, is built through precisely orchestrated waves of newly born neurons that migrate past their precursors (2, 4). This orderly acquisition of the different neural lineages is mediated by specific networks of transcriptional activators and repressors in response to environmental and intrinsic cues (for reviews see refs. 3, 5, and 6). How the precise timing of this signaling cascade is accomplished and whether migration and differentiation are linked obligatorily during development is still obscure.One key factor in this process could be the transcriptional repressor REST (also called NRSF), which regulates a large number of neuronal genes as well as brain-specific microRNA genes (7-11). In nonneuronal cells, REST binds to a conserved 23-bp DNA motif known as RE1 (repressor element 1), located in the regulatory regions of these genes, and blocks their transcription, via the corepressors . We showed previously that REST repression in pluripotent ES cells and multipotent neural stem/progenitor (NS/P) cells creates a chromatin status poised for subsequent activation (12,14). Importantly, REST itself is regulated differentially throughout development, expressed to high levels in ES cells but present in minimal levels in NS/P cells. The down-regulation of REST in NS/P cells is mediated, at least in part, by targeted proteasomal degradation via the E3 ubiquitin ligase β-TRCP (15, 12). As NS/P cells diffe...

An RNA Binding Protein Promotes Axonal Integrity in Peripheral Neurons by Destabilizing REST

“…Predictably, REST is downregulated during neurogenesis, at both the mRNA and protein levels, to allow these genes to be expressed (Ballas et al, 2005;Guardavaccaro et al, 2008;Westbrook et al, 2008;Gao et al, 2011). Forced expression of REST during neurogenesis results in defects in cortical migration and axonal pathfinding (Paquette et al, 2000;Mandel et al, 2011). Consistent with these observations, Rest promoter activity is itself repressed in some postmitotic cortical neurons (Ballas et al, 2005).…”

“…For example, in adult mouse hippocampus, Rest transcripts are upregulated in response to ischemic insult (Kokaia et al, 1994) and are proposed to contribute to cell death through regulation of glutamate excitotoxicity (Calderone et al, 2003). Rest mRNA levels and RE1 occupancy of REST target genes also increase in peripheral neurons in response to nociceptive stimuli (Michaelevski et al, 2010;Uchida et al, 2010;Ben-Yaakov et al, 2012) and have been associated with epilepsy (McClelland et al, 2011;Pozzi et al, 2013). Mechanisms that regulate Rest mRNA levels in these different functional contexts are unknown, but an early study (Kojima et al, 2001) reported that cell type-specific expression of REST was not strictly promoter-dependent, and our studies herein support the suggestion of post-transcriptional regulation.…”

C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation

“…Both mutant ERK phenotypes would be predicted by stabilization of REST through loss of ERK1/2 phosphorylation of S861/864. A similar differentiationarrested phenotype was also observed after persistent expression of REST in neural progenitors in vivo (26). REST expression has been reported in adult brain (27,28) as well as in neural progenitors during neurogenesis.…”

Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death

“…As neural progenitors differentiate into neurons, REST and its corepressors depart the RE1 site of selected neuronal genes, triggering transcriptional activation. In newborn neurons, the level of expression of REST targets is adjusted further by CoREST-MeCP2 repressor complexes, which remain bound after REST (8,49). A recent study suggests that MeCP2 localizes to nearly every nucleosome and, as such, may not bind preferentially to individual genes (50).…”