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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

Expression of REST in various cell types in the human brain. Sequential slices were dually immunolabeled with an anti-REST antibody (green) together with antibodies against markers of various cell types (red). The REST immunolabeling is different in the various panels. A, In neurons, no appreciable REST immunolabeling is present. B, In microglia, nuclear REST immunolabeling is strong. C, In astrocytes, nuclear REST immunolabeling is variable. C', C'', Enlargements of the immunolabeling in the boxes in C, confirming the variable REST immunolabeling in the nuclei of astrocytes. D, Quantification of the nuclear REST data illustrated in A–C is shown. Scale bar: (in C) A–C, 30 μm. The figure is from Prada et al., 2011.
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Figure 1: Expression of REST in various cell types in the human brain. Sequential slices were dually immunolabeled with an anti-REST antibody (green) together with antibodies against markers of various cell types (red). The REST immunolabeling is different in the various panels. A, In neurons, no appreciable REST immunolabeling is present. B, In microglia, nuclear REST immunolabeling is strong. C, In astrocytes, nuclear REST immunolabeling is variable. C', C'', Enlargements of the immunolabeling in the boxes in C, confirming the variable REST immunolabeling in the nuclei of astrocytes. D, Quantification of the nuclear REST data illustrated in A–C is shown. Scale bar: (in C) A–C, 30 μm. The figure is from Prada et al., 2011.

Mentions: The downregulation of REST is critical for the acquisition and preservation of neuronal specificities. The expression of REST-dependent genes activates a variety of important processes during advanced differentiation, such as axonal growth, the establishment of synaptic contacts, and membrane excitability (Paquette et al., 2000; Aoki et al., 2012). In the adult brain, all neurons exhibit low levels of REST (Fig. 1), although with some moderate heterogeneity (Palm et al., 1998; Calderone et al., 2003; Sun et al., 2005; Gao et al., 2011). Compared to the case in stem cells, the number of REST target genes is lower in adult neurons. The decrease of these genes, which is established during differentiation, is mostly a consequence of chromatin remodeling that reduces gene access to transcription (Murai et al., 2005; Abrajano et al., 2009; Yoo et al., 2009; Juliandi et al., 2010, Johnson et al., 2012).


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

Baldelli P, Meldolesi J - eNeuro (2015)

Expression of REST in various cell types in the human brain. Sequential slices were dually immunolabeled with an anti-REST antibody (green) together with antibodies against markers of various cell types (red). The REST immunolabeling is different in the various panels. A, In neurons, no appreciable REST immunolabeling is present. B, In microglia, nuclear REST immunolabeling is strong. C, In astrocytes, nuclear REST immunolabeling is variable. C', C'', Enlargements of the immunolabeling in the boxes in C, confirming the variable REST immunolabeling in the nuclei of astrocytes. D, Quantification of the nuclear REST data illustrated in A–C is shown. Scale bar: (in C) A–C, 30 μm. The figure is from Prada et al., 2011.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Expression of REST in various cell types in the human brain. Sequential slices were dually immunolabeled with an anti-REST antibody (green) together with antibodies against markers of various cell types (red). The REST immunolabeling is different in the various panels. A, In neurons, no appreciable REST immunolabeling is present. B, In microglia, nuclear REST immunolabeling is strong. C, In astrocytes, nuclear REST immunolabeling is variable. C', C'', Enlargements of the immunolabeling in the boxes in C, confirming the variable REST immunolabeling in the nuclei of astrocytes. D, Quantification of the nuclear REST data illustrated in A–C is shown. Scale bar: (in C) A–C, 30 μm. The figure is from Prada et al., 2011.
Mentions: The downregulation of REST is critical for the acquisition and preservation of neuronal specificities. The expression of REST-dependent genes activates a variety of important processes during advanced differentiation, such as axonal growth, the establishment of synaptic contacts, and membrane excitability (Paquette et al., 2000; Aoki et al., 2012). In the adult brain, all neurons exhibit low levels of REST (Fig. 1), although with some moderate heterogeneity (Palm et al., 1998; Calderone et al., 2003; Sun et al., 2005; Gao et al., 2011). Compared to the case in stem cells, the number of REST target genes is lower in adult neurons. The decrease of these genes, which is established during differentiation, is mostly a consequence of chromatin remodeling that reduces gene access to transcription (Murai et al., 2005; Abrajano et al., 2009; Yoo et al., 2009; Juliandi et al., 2010, Johnson et al., 2012).

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