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The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases(1,2,3).

Baldelli P, Meldolesi J - eNeuro (2015)

Bottom Line: Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity.In conclusion, REST is certainly very important in a large number of conditions.We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medicine, University of Genova , 16163 Genova, Italy ; Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia , 16132 Genova, Italy.

ABSTRACT
REST [RE1-silencing transcription factor (also called neuron-restrictive silencer factor)] is known to repress thousands of possible target genes, many of which are neuron specific. To date, REST repression has been investigated mostly in stem cells and differentiating neurons. Current evidence demonstrates its importance in adult neurons as well. Low levels of REST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend on miRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains a subject of debate. Examples of CA1 hippocampal neuron protection upon depolarization, and of neurodegeneration upon glutamate treatment and hypoxia have been reported. REST participation in psychiatric and neurological diseases has been shown, especially in Alzheimer's disease and Huntington's disease, as well as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

No MeSH data available.


Related in: MedlinePlus

4-Aminopyridine (4AP)-induced cortical neuron hyperactivity increases REST expression and, in parallel, downregulates the expression of the Na+ channel Nav1.2. A, Analysis of REST (blue). Top, Quantitative RT-PCR analysis of REST mRNA levels in cortical neurons that were either untreated or treated with 4AP (100 μm) for 24, 48, and 96 h. Bottom, Changes in the REST protein of cortical neurons treated as in the top panel, quantified by Western blotting. B, Analysis of Nav1.2 (red). Top, Quantitative RT-PCR of the changes in Nav1.2 mRNA in cortical neurons, which were untreated or treated with 4AP as in A. Bottom, Nav1.2 protein of cortical neurons treated as in A, quantified by Western blotting. Notice that, for both mRNA and protein, the opposite changes were induced by 4AP: an increase in REST mRNA at 24 h, followed by a decrease back to the untreated level at 96 h, accompanied by a decrease of Nav1.2 mRNA, and followed by an increase at the same times; and a slow increase in REST protein (up to approximately eightfold at 96 h) accompanied by a slow decrease in Nav1.2 (∼40% at 96 h). The data in the columns in A and B (mean ± SEM) were obtained from seven to eight (top) and four (bottom) samples from two separate neuronal preparations. *p < 0.05, Kruskal–Wallis test followed by Dunn's test versus untreated. The figure is from Pozzi et al., 2013.
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Figure 2: 4-Aminopyridine (4AP)-induced cortical neuron hyperactivity increases REST expression and, in parallel, downregulates the expression of the Na+ channel Nav1.2. A, Analysis of REST (blue). Top, Quantitative RT-PCR analysis of REST mRNA levels in cortical neurons that were either untreated or treated with 4AP (100 μm) for 24, 48, and 96 h. Bottom, Changes in the REST protein of cortical neurons treated as in the top panel, quantified by Western blotting. B, Analysis of Nav1.2 (red). Top, Quantitative RT-PCR of the changes in Nav1.2 mRNA in cortical neurons, which were untreated or treated with 4AP as in A. Bottom, Nav1.2 protein of cortical neurons treated as in A, quantified by Western blotting. Notice that, for both mRNA and protein, the opposite changes were induced by 4AP: an increase in REST mRNA at 24 h, followed by a decrease back to the untreated level at 96 h, accompanied by a decrease of Nav1.2 mRNA, and followed by an increase at the same times; and a slow increase in REST protein (up to approximately eightfold at 96 h) accompanied by a slow decrease in Nav1.2 (∼40% at 96 h). The data in the columns in A and B (mean ± SEM) were obtained from seven to eight (top) and four (bottom) samples from two separate neuronal preparations. *p < 0.05, Kruskal–Wallis test followed by Dunn's test versus untreated. The figure is from Pozzi et al., 2013.

Mentions: Neuronal excitation is also controlled by REST. Prolonged in vitro depolarization of neuronal primary cultures with high extracellular K+ was reported to induce increases in REST accompanied by the downregulation of proteins encoded by target genes, including the neurotrophin BDNF (Hara et al, 2009) and the transcription factor NPAS4 (Bersten et al., 2014). Similar results were obtained when depolarization was induced in primary cultures of mouse hippocampal neurons by up to 4 days of treatment with 4-aminopyridine, a blocker of K+ channels. The treatment, the effects of which were analyzed by patch-clamp and multielectrode array recordings, was shown to induce, in excitatory neurons, a transient increase in REST mRNA followed by an increase in the protein (Fig. 2A) and a progressive decline in action potential frequency (Pozzi et al., 2013). The effect was due to the decrease in both the firing frequency and density of Na+ channels, which were identified as Nav1.2 channels (Fig. 2B). This decreased excitability corresponds to the decline of a well known neuronal condition, intrinsic homeostasis (Pozzi et al., 2013).


The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases(1,2,3).

Baldelli P, Meldolesi J - eNeuro (2015)

4-Aminopyridine (4AP)-induced cortical neuron hyperactivity increases REST expression and, in parallel, downregulates the expression of the Na+ channel Nav1.2. A, Analysis of REST (blue). Top, Quantitative RT-PCR analysis of REST mRNA levels in cortical neurons that were either untreated or treated with 4AP (100 μm) for 24, 48, and 96 h. Bottom, Changes in the REST protein of cortical neurons treated as in the top panel, quantified by Western blotting. B, Analysis of Nav1.2 (red). Top, Quantitative RT-PCR of the changes in Nav1.2 mRNA in cortical neurons, which were untreated or treated with 4AP as in A. Bottom, Nav1.2 protein of cortical neurons treated as in A, quantified by Western blotting. Notice that, for both mRNA and protein, the opposite changes were induced by 4AP: an increase in REST mRNA at 24 h, followed by a decrease back to the untreated level at 96 h, accompanied by a decrease of Nav1.2 mRNA, and followed by an increase at the same times; and a slow increase in REST protein (up to approximately eightfold at 96 h) accompanied by a slow decrease in Nav1.2 (∼40% at 96 h). The data in the columns in A and B (mean ± SEM) were obtained from seven to eight (top) and four (bottom) samples from two separate neuronal preparations. *p < 0.05, Kruskal–Wallis test followed by Dunn's test versus untreated. The figure is from Pozzi et al., 2013.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4596026&req=5

Figure 2: 4-Aminopyridine (4AP)-induced cortical neuron hyperactivity increases REST expression and, in parallel, downregulates the expression of the Na+ channel Nav1.2. A, Analysis of REST (blue). Top, Quantitative RT-PCR analysis of REST mRNA levels in cortical neurons that were either untreated or treated with 4AP (100 μm) for 24, 48, and 96 h. Bottom, Changes in the REST protein of cortical neurons treated as in the top panel, quantified by Western blotting. B, Analysis of Nav1.2 (red). Top, Quantitative RT-PCR of the changes in Nav1.2 mRNA in cortical neurons, which were untreated or treated with 4AP as in A. Bottom, Nav1.2 protein of cortical neurons treated as in A, quantified by Western blotting. Notice that, for both mRNA and protein, the opposite changes were induced by 4AP: an increase in REST mRNA at 24 h, followed by a decrease back to the untreated level at 96 h, accompanied by a decrease of Nav1.2 mRNA, and followed by an increase at the same times; and a slow increase in REST protein (up to approximately eightfold at 96 h) accompanied by a slow decrease in Nav1.2 (∼40% at 96 h). The data in the columns in A and B (mean ± SEM) were obtained from seven to eight (top) and four (bottom) samples from two separate neuronal preparations. *p < 0.05, Kruskal–Wallis test followed by Dunn's test versus untreated. The figure is from Pozzi et al., 2013.
Mentions: Neuronal excitation is also controlled by REST. Prolonged in vitro depolarization of neuronal primary cultures with high extracellular K+ was reported to induce increases in REST accompanied by the downregulation of proteins encoded by target genes, including the neurotrophin BDNF (Hara et al, 2009) and the transcription factor NPAS4 (Bersten et al., 2014). Similar results were obtained when depolarization was induced in primary cultures of mouse hippocampal neurons by up to 4 days of treatment with 4-aminopyridine, a blocker of K+ channels. The treatment, the effects of which were analyzed by patch-clamp and multielectrode array recordings, was shown to induce, in excitatory neurons, a transient increase in REST mRNA followed by an increase in the protein (Fig. 2A) and a progressive decline in action potential frequency (Pozzi et al., 2013). The effect was due to the decrease in both the firing frequency and density of Na+ channels, which were identified as Nav1.2 channels (Fig. 2B). This decreased excitability corresponds to the decline of a well known neuronal condition, intrinsic homeostasis (Pozzi et al., 2013).

Bottom Line: Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity.In conclusion, REST is certainly very important in a large number of conditions.We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medicine, University of Genova , 16163 Genova, Italy ; Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia , 16132 Genova, Italy.

ABSTRACT
REST [RE1-silencing transcription factor (also called neuron-restrictive silencer factor)] is known to repress thousands of possible target genes, many of which are neuron specific. To date, REST repression has been investigated mostly in stem cells and differentiating neurons. Current evidence demonstrates its importance in adult neurons as well. Low levels of REST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend on miRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulation with various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains a subject of debate. Examples of CA1 hippocampal neuron protection upon depolarization, and of neurodegeneration upon glutamate treatment and hypoxia have been reported. REST participation in psychiatric and neurological diseases has been shown, especially in Alzheimer's disease and Huntington's disease, as well as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that the conflicting results reported for the role of REST in physiology, pathology, and disease depend on its complex, direct, and indirect actions on many gene targets and on the diverse approaches used during the investigations.

No MeSH data available.


Related in: MedlinePlus