BMP-induced REST regulates the establishment and maintenance of astrocytic identity

Kohyama, Jun; Sanosaka, Tsukasa; Tokunaga, Akinori; Takatsuka, Eriko; Tsujimura, Keita; Okano, Hideyuki; Nakashima, Kinichi

doi:10.1083/jcb.200908048

Cited by 82 publications

(83 citation statements)

References 64 publications

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“…Despite the fact that the arrested cells were localized to the white matter where glial cells normally reside, and that normally glia and not neurons retain REST (22), these cells unexpectedly differentiated into neurons. This finding is surprising because REST is a repressor of neuronal-trait genes, suggesting that the REST-expressing cells circumvented the presence of REST and initiated neurogenesis, albeit with a delay.…”

Section: Discussionmentioning

confidence: 99%

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

Mandel

Fiondella

Covey

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 99%

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

Mandel

Fiondella

Covey

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…37 In addition, REST is modulated by multiple developmental cues, including patterning and specification factors (e.g., RA, BMP and WNT). 38,39 These observations imply that REST acts as a regulator of multiple stages of embryonic and neural development through precise regulation of neural developmental genes.…”

Section: Rest and Corest In Developmental Processesmentioning

confidence: 99%

“…Our observations are consistent with a subsequent study demonstrating that BMP signaling upregulates REST expression which, in turn, promotes astroglial lineage specification and maintenance. 39 We also identified other REST and CoREST target genes responsible for mediating a broad array of biological processes that may be involved in determining glial cell identity and function. These included numerous epigenetic (e.g., Hist1 h4a, Mbd6, Scmh1, Smarca2 and Smc4l1) and cell cycle regulatory (e.g., Ccna2, Ccnd1, Cdc34, Cdk5r1 and Cdkn2c) genes as well as many classes of cell surface identity (e.g., protocadherin, olfactory receptors, vomeronasal receptors and cell adhesion and additional transmembrane proteins) factors.…”

mentioning

confidence: 99%

REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions

Qureshi

Gökhan²,

Mehler³

2010

Cell Cycle

126

107

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“…Together, these findings led to the notion that the switch from the self-renewal stage to the neurogenic stage of precursor cells (Figure 1) is dependent upon the downregulation of REST by SCF--TrCP (Figure 3c). Although REST also plays a role in glia cell differentiation, it is unclear if ubiquitination of REST by SCF--TrCP is also involved in gliogenesis 68 .…”

Section: Regulation Of Proneural Gene Expression By Ubiquitination-dementioning

confidence: 99%

The role of ubiquitylation in nerve cell development

2011

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| Nerve cell development in the brain is a tightly regulated process. The generation of neurons from precursor cells, their migration to the appropriate target sites, their extensive arborisation, and their integration into functional networks through synapse formation and refinement are governed by multiple interdependent signaling cascades. The function and turnover of proteins involved in these signaling cascades, in turn, are spatially and temporally controlled by ubiquitination. Recent advances have provided first insights into the highly complex and intricate molecular pathways that regulate ubiquitination during all stages of neural development and operate in parallel with other regulatory processes such as phosphorylation or cyclic nucleotide signaling.

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BMP-induced REST regulates the establishment and maintenance of astrocytic identity

Abstract: Astrocyte differentiation and maintenance is promoted by BMP signaling, which induces REST/NRSF to repress neuronal genes.

Cited by 82 publications

References 64 publications

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

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

REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions

The role of ubiquitylation in nerve cell development

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