The RE1 Binding Protein REST Regulates Oligodendrocyte Differentiation

DeWald, Lisa Evans; Rodriguez, Justin P.; Levine, Joel M.

doi:10.1523/jneurosci.2768-10.2011

Cited by 33 publications

(36 citation statements)

References 73 publications

(105 reference statements)

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“…The zebrafish rest mutant phenotype resembles the mouse Olig1 knockout, in which early deficits of OPCs are subsequently overcome (Lu et al, 2002). Recent studies have provided evidence that Rest regulates glial differentiation, including emergence of oligodendrocytes (Abrajano et al, 2009;DeWald et al, 2011;Soldati et al, 2012). Our in vivo results implicate Rest-regulated gene expression in the development of the OPC lineage in zebrafish.…”

Section: Research Articlementioning

confidence: 53%

Zebrafish rest regulates developmental gene expression but not neurogenesis

et al. 2012

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SUMMARYThe transcriptional repressor Rest (Nrsf) recruits chromatin-modifying complexes to RE1 'silencer elements', which are associated with hundreds of neural genes. However, the requirement for Rest-mediated transcriptional regulation of embryonic development and cell fate is poorly understood. Conflicting views of the role of Rest in controlling cell fate have emerged from recent studies. To address these controversies, we examined the developmental requirement for Rest in zebrafish using zinc-finger nucleasemediated gene targeting. We discovered that germ layer specification progresses normally in rest mutants despite derepression of target genes during embryogenesis. This analysis provides the first evidence that maternal rest is essential for repression of target genes during blastula stages. Surprisingly, neurogenesis proceeds largely normally in rest mutants, although abnormalities are observed within the nervous system, including defects in oligodendrocyte precursor cell development and a partial loss of facial branchiomotor neuron migration. Mutants progress normally through embryogenesis but many die as larvae (after 12 days). However, some homozygotes reach adulthood and are viable. We utilized an RE1/NRSE transgenic reporter system to dynamically monitor Rest activity. This analysis revealed that Rest is required to repress gene expression in mesodermal derivatives including muscle and notochord, as well as within the nervous system. Finally, we demonstrated that Rest is required for long-term repression of target genes in non-neural tissues in adult zebrafish. Our results point to a broad role for Rest in fine-tuning neural gene expression, rather than as a widespread regulator of neurogenesis or cell fate.

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Section: Research Articlementioning

confidence: 53%

Zebrafish rest regulates developmental gene expression but not neurogenesis

et al. 2012

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“…Importantly, REST itself is differentially regulated throughout neural development; whereas REST is expressed at a high level in ES cells, it is downregulated to a minimal level in NS/P cells. As NS/P cells differentiate, REST remains present in glia (Abrajano et al, 2009;Dewald et al, 2011) but is largely absent in neurons, allowing the restricted expression of its target genes specifically in neurons . Whereas the high level of REST expression in ES cells is mediated by NANOG and OCT4 (POU5F1 -Mouse Genome Informatics)) (Boyer et al, 2005;Loh et al, 2006), the low level in NS/P cells is mediated, at least in part, by proteasomal degradation via the E3 ubiquitin ligase -TRCP (BTRC -Mouse Genome Informatics) (Ballas et al, Here, we analyzed the function of REST at different stages of neural development and show that, although the high level of REST in ES cells is essential for its full functioning as a repressor of neuronal genes, neither REST nor CoREST is required for maintaining ES cell pluripotency.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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

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“…Cultures were fixed and stained as described previously (Dewald et al, 2011). Primary antibodies were polyclonal anti-PKC (1:200; Santa Cruz Biotechnology), anti-Par3 (1:100; Millipore), monoclonal anti-Tau (1: 100; Millipore), Neuronal Class III ␤-tubulin (Tuj1) monoclonal antibody (1:500; Covance), and anti-GAP43 (1:5000; gift from D. Schreyer, University of Saskatoon, Saskatoon, SK, Canada).…”

Section: Immunocytochemistrymentioning

confidence: 99%

“…NG2 is secreted or shed predominantly from reactive oligodendrocyte precursor cells and reaches maximum levels at injury sites within 5-7 d after injury. NG2 inhibits axon growth in vitro, forms barriers to axon extension, and induces growth cone collapse (Dou and Fidler et al, 1999;Chen et al, 2002;Ughrin et al, 2003), although these findings remain controversial (Yang et al, 2006a;Busch et al, 2010). After spinal cord injury, the dystrophic ends of damaged axons are embedded in NG2-rich regions of the glial scar (Jones et al, 2002), and the infusion of function-blocking antibodies against NG2 allows sensory axons to grow into and out of an injury site (Tan et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Atypical Protein Kinase C and Par3 Are Required for Proteoglycan-Induced Axon Growth Inhibition

et al. 2013

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When the CNS is injured, damaged axons do not regenerate. This failure is due in part to the growth-inhibitory environment that forms at the injury site. Myelin-associated molecules, repulsive axon guidance molecules, and extracellular matrix molecules including chondroitin sulfate proteoglycans (CSPGs) found within the glial scar inhibit axon regeneration but the intracellular signaling mechanisms triggered by these diverse molecules remain largely unknown. Here we provide biochemical and functional evidence that atypical protein kinase C (PKC) and polarity (Par) complex proteins mediate axon growth inhibition. Treatment of postnatal rat neurons in vitro with the NG2 CSPG, a major component of the glial scar, activates PKC, and this activation is both necessary and sufficient to inhibit axonal growth. NG2 treatment also activates Cdc42, increases the association of Par6 with PKC, and leads to a Par3-dependent activation of Rac1. Transfection of neurons with kinase-dead forms of PKC, dominant-negative forms of Cdc42, or mutant forms of Par6 that do not bind to Cdc42 prevent NG2-induced growth inhibition. Similarly, transfection with either a phosphomutant Par3 (S824A) or dominantnegative Rac1 prevent inhibition, whereas expression of constitutively active Rac1 inhibits axon growth on control surfaces. These results suggest a model in which NG2 binding to neurons activates PKC and modifies Par complex function. They also identify the Par complex as a novel therapeutic target for promoting axon regeneration after CNS injury.

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The RE1 Binding Protein REST Regulates Oligodendrocyte Differentiation

Cited by 33 publications

References 73 publications

Zebrafish rest regulates developmental gene expression but not neurogenesis

Zebrafish rest regulates developmental gene expression but not neurogenesis

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

Atypical Protein Kinase C and Par3 Are Required for Proteoglycan-Induced Axon Growth Inhibition

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