Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome

Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and col...
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Autor*in:	Bhattacherjee, Aritra [verfasserIn] Mu, Ying Winter, Michelle K Knapp, Jennifer R Eggimann, Linda S Gunewardena, Sumedha S Kobayashi, Kazuto Kato, Shigeki Agbas, Dora Krizsan Smith, Peter G

Format:	Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	Rett syndrome Development and progression Health aspects Gene mutations Care and treatment Genetic regulation Binding proteins Genetic aspects Nociception Neurological disorders Molecular modelling Polymerization Pain sensitivity Dorsal root ganglia Pain Rats Cold stimuli Cytoskeleton Gene expression Hypersensitivity Genes Cadherin Axonogenesis Actin MeCP2 protein Rodents Innervation Sensitivity Cold pressing Axon sprouting Sensory neurons Subpopulations CpG islands Children Adhesion Methyl-CpG binding protein Neurons Gene regulation Axons Abnormalities Signal transduction

Übergeordnetes Werk:	Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 114(2017), 33, Seite E6952
Übergeordnetes Werk:	volume:114 ; year:2017 ; number:33 ; pages:E6952

Links:	Volltext Link aufrufen

DOI / URN:	10.1073/pnas.1618210114

Katalog-ID:	OLC1998533565

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520			\|a Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.
650		4	\|a Rett syndrome
650		4	\|a Development and progression
650		4	\|a Health aspects
650		4	\|a Gene mutations
650		4	\|a Care and treatment
650		4	\|a Genetic regulation
650		4	\|a Binding proteins
650		4	\|a Genetic aspects
650		4	\|a Nociception
650		4	\|a Neurological disorders
650		4	\|a Molecular modelling
650		4	\|a Polymerization
650		4	\|a Pain sensitivity
650		4	\|a Dorsal root ganglia
650		4	\|a Pain
650		4	\|a Rats
650		4	\|a Cold stimuli
650		4	\|a Cytoskeleton
650		4	\|a Gene expression
650		4	\|a Hypersensitivity
650		4	\|a Genes
650		4	\|a Cadherin
650		4	\|a Axonogenesis
650		4	\|a Actin
650		4	\|a MeCP2 protein
650		4	\|a Rodents
650		4	\|a Innervation
650		4	\|a Sensitivity
650		4	\|a Cold pressing
650		4	\|a Axon sprouting
650		4	\|a Sensory neurons
650		4	\|a Subpopulations
650		4	\|a CpG islands
650		4	\|a Children
650		4	\|a Adhesion
650		4	\|a Methyl-CpG binding protein
650		4	\|a Neurons
650		4	\|a Gene regulation
650		4	\|a Axons
650		4	\|a Abnormalities
650		4	\|a Signal transduction
700	1		\|a Mu, Ying \|4 oth
700	1		\|a Winter, Michelle K \|4 oth
700	1		\|a Knapp, Jennifer R \|4 oth
700	1		\|a Eggimann, Linda S \|4 oth
700	1		\|a Gunewardena, Sumedha S \|4 oth
700	1		\|a Kobayashi, Kazuto \|4 oth
700	1		\|a Kato, Shigeki \|4 oth
700	1		\|a Agbas, Dora Krizsan \|4 oth
700	1		\|a Smith, Peter G \|4 oth
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856	4	1	\|u http://dx.doi.org/10.1073/pnas.1618210114 \|3 Volltext
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allfields	10.1073/pnas.1618210114 doi PQ20171228 (DE-627)OLC1998533565 (DE-599)GBVOLC1998533565 (PRQ)g1168-31141245ffab7f90c199323260c975409a7147d63dee4a79b68c440acd2d48c20 (KEY)0583363920170000114003306952neuronalcytoskeletalgenedysregulationandmechanical DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Bhattacherjee, Aritra verfasserin aut Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome. Rett syndrome Development and progression Health aspects Gene mutations Care and treatment Genetic regulation Binding proteins Genetic aspects Nociception Neurological disorders Molecular modelling Polymerization Pain sensitivity Dorsal root ganglia Pain Rats Cold stimuli Cytoskeleton Gene expression Hypersensitivity Genes Cadherin Axonogenesis Actin MeCP2 protein Rodents Innervation Sensitivity Cold pressing Axon sprouting Sensory neurons Subpopulations CpG islands Children Adhesion Methyl-CpG binding protein Neurons Gene regulation Axons Abnormalities Signal transduction Mu, Ying oth Winter, Michelle K oth Knapp, Jennifer R oth Eggimann, Linda S oth Gunewardena, Sumedha S oth Kobayashi, Kazuto oth Kato, Shigeki oth Agbas, Dora Krizsan oth Smith, Peter G oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 33, Seite E6952 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:33 pages:E6952 http://dx.doi.org/10.1073/pnas.1618210114 Volltext https://search.proquest.com/docview/1946454963 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 33 E6952
spelling	10.1073/pnas.1618210114 doi PQ20171228 (DE-627)OLC1998533565 (DE-599)GBVOLC1998533565 (PRQ)g1168-31141245ffab7f90c199323260c975409a7147d63dee4a79b68c440acd2d48c20 (KEY)0583363920170000114003306952neuronalcytoskeletalgenedysregulationandmechanical DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Bhattacherjee, Aritra verfasserin aut Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome. Rett syndrome Development and progression Health aspects Gene mutations Care and treatment Genetic regulation Binding proteins Genetic aspects Nociception Neurological disorders Molecular modelling Polymerization Pain sensitivity Dorsal root ganglia Pain Rats Cold stimuli Cytoskeleton Gene expression Hypersensitivity Genes Cadherin Axonogenesis Actin MeCP2 protein Rodents Innervation Sensitivity Cold pressing Axon sprouting Sensory neurons Subpopulations CpG islands Children Adhesion Methyl-CpG binding protein Neurons Gene regulation Axons Abnormalities Signal transduction Mu, Ying oth Winter, Michelle K oth Knapp, Jennifer R oth Eggimann, Linda S oth Gunewardena, Sumedha S oth Kobayashi, Kazuto oth Kato, Shigeki oth Agbas, Dora Krizsan oth Smith, Peter G oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 33, Seite E6952 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:33 pages:E6952 http://dx.doi.org/10.1073/pnas.1618210114 Volltext https://search.proquest.com/docview/1946454963 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 33 E6952
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allfieldsSound	10.1073/pnas.1618210114 doi PQ20171228 (DE-627)OLC1998533565 (DE-599)GBVOLC1998533565 (PRQ)g1168-31141245ffab7f90c199323260c975409a7147d63dee4a79b68c440acd2d48c20 (KEY)0583363920170000114003306952neuronalcytoskeletalgenedysregulationandmechanical DE-627 ger DE-627 rakwb eng 500 DE-101 570 AVZ LING fid BIODIV fid Bhattacherjee, Aritra verfasserin aut Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome. Rett syndrome Development and progression Health aspects Gene mutations Care and treatment Genetic regulation Binding proteins Genetic aspects Nociception Neurological disorders Molecular modelling Polymerization Pain sensitivity Dorsal root ganglia Pain Rats Cold stimuli Cytoskeleton Gene expression Hypersensitivity Genes Cadherin Axonogenesis Actin MeCP2 protein Rodents Innervation Sensitivity Cold pressing Axon sprouting Sensory neurons Subpopulations CpG islands Children Adhesion Methyl-CpG binding protein Neurons Gene regulation Axons Abnormalities Signal transduction Mu, Ying oth Winter, Michelle K oth Knapp, Jennifer R oth Eggimann, Linda S oth Gunewardena, Sumedha S oth Kobayashi, Kazuto oth Kato, Shigeki oth Agbas, Dora Krizsan oth Smith, Peter G oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 114(2017), 33, Seite E6952 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:114 year:2017 number:33 pages:E6952 http://dx.doi.org/10.1073/pnas.1618210114 Volltext https://search.proquest.com/docview/1946454963 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 114 2017 33 E6952
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source	Enthalten in Proceedings of the National Academy of Sciences of the United States of America 114(2017), 33, Seite E6952 volume:114 year:2017 number:33 pages:E6952
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topic_facet	Rett syndrome Development and progression Health aspects Gene mutations Care and treatment Genetic regulation Binding proteins Genetic aspects Nociception Neurological disorders Molecular modelling Polymerization Pain sensitivity Dorsal root ganglia Pain Rats Cold stimuli Cytoskeleton Gene expression Hypersensitivity Genes Cadherin Axonogenesis Actin MeCP2 protein Rodents Innervation Sensitivity Cold pressing Axon sprouting Sensory neurons Subpopulations CpG islands Children Adhesion Methyl-CpG binding protein Neurons Gene regulation Axons Abnormalities Signal transduction
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author	Bhattacherjee, Aritra
spellingShingle	Bhattacherjee, Aritra ddc 500 ddc 570 fid LING fid BIODIV misc Rett syndrome misc Development and progression misc Health aspects misc Gene mutations misc Care and treatment misc Genetic regulation misc Binding proteins misc Genetic aspects misc Nociception misc Neurological disorders misc Molecular modelling misc Polymerization misc Pain sensitivity misc Dorsal root ganglia misc Pain misc Rats misc Cold stimuli misc Cytoskeleton misc Gene expression misc Hypersensitivity misc Genes misc Cadherin misc Axonogenesis misc Actin misc MeCP2 protein misc Rodents misc Innervation misc Sensitivity misc Cold pressing misc Axon sprouting misc Sensory neurons misc Subpopulations misc CpG islands misc Children misc Adhesion misc Methyl-CpG binding protein misc Neurons misc Gene regulation misc Axons misc Abnormalities misc Signal transduction Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome
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topic_title	500 DE-101 570 AVZ LING fid BIODIV fid Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome Rett syndrome Development and progression Health aspects Gene mutations Care and treatment Genetic regulation Binding proteins Genetic aspects Nociception Neurological disorders Molecular modelling Polymerization Pain sensitivity Dorsal root ganglia Pain Rats Cold stimuli Cytoskeleton Gene expression Hypersensitivity Genes Cadherin Axonogenesis Actin MeCP2 protein Rodents Innervation Sensitivity Cold pressing Axon sprouting Sensory neurons Subpopulations CpG islands Children Adhesion Methyl-CpG binding protein Neurons Gene regulation Axons Abnormalities Signal transduction
topic	ddc 500 ddc 570 fid LING fid BIODIV misc Rett syndrome misc Development and progression misc Health aspects misc Gene mutations misc Care and treatment misc Genetic regulation misc Binding proteins misc Genetic aspects misc Nociception misc Neurological disorders misc Molecular modelling misc Polymerization misc Pain sensitivity misc Dorsal root ganglia misc Pain misc Rats misc Cold stimuli misc Cytoskeleton misc Gene expression misc Hypersensitivity misc Genes misc Cadherin misc Axonogenesis misc Actin misc MeCP2 protein misc Rodents misc Innervation misc Sensitivity misc Cold pressing misc Axon sprouting misc Sensory neurons misc Subpopulations misc CpG islands misc Children misc Adhesion misc Methyl-CpG binding protein misc Neurons misc Gene regulation misc Axons misc Abnormalities misc Signal transduction
topic_unstemmed	ddc 500 ddc 570 fid LING fid BIODIV misc Rett syndrome misc Development and progression misc Health aspects misc Gene mutations misc Care and treatment misc Genetic regulation misc Binding proteins misc Genetic aspects misc Nociception misc Neurological disorders misc Molecular modelling misc Polymerization misc Pain sensitivity misc Dorsal root ganglia misc Pain misc Rats misc Cold stimuli misc Cytoskeleton misc Gene expression misc Hypersensitivity misc Genes misc Cadherin misc Axonogenesis misc Actin misc MeCP2 protein misc Rodents misc Innervation misc Sensitivity misc Cold pressing misc Axon sprouting misc Sensory neurons misc Subpopulations misc CpG islands misc Children misc Adhesion misc Methyl-CpG binding protein misc Neurons misc Gene regulation misc Axons misc Abnormalities misc Signal transduction
topic_browse	ddc 500 ddc 570 fid LING fid BIODIV misc Rett syndrome misc Development and progression misc Health aspects misc Gene mutations misc Care and treatment misc Genetic regulation misc Binding proteins misc Genetic aspects misc Nociception misc Neurological disorders misc Molecular modelling misc Polymerization misc Pain sensitivity misc Dorsal root ganglia misc Pain misc Rats misc Cold stimuli misc Cytoskeleton misc Gene expression misc Hypersensitivity misc Genes misc Cadherin misc Axonogenesis misc Actin misc MeCP2 protein misc Rodents misc Innervation misc Sensitivity misc Cold pressing misc Axon sprouting misc Sensory neurons misc Subpopulations misc CpG islands misc Children misc Adhesion misc Methyl-CpG binding protein misc Neurons misc Gene regulation misc Axons misc Abnormalities misc Signal transduction
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title	Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome
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title_full	Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome
author_sort	Bhattacherjee, Aritra
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title_sort	neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of rett syndrome
title_auth	Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome
abstract	Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.
abstractGer	Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.
abstract_unstemmed	Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.
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title_short	Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome
url	http://dx.doi.org/10.1073/pnas.1618210114 https://search.proquest.com/docview/1946454963
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author2	Mu, Ying Winter, Michelle K Knapp, Jennifer R Eggimann, Linda S Gunewardena, Sumedha S Kobayashi, Kazuto Kato, Shigeki Agbas, Dora Krizsan Smith, Peter G
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up_date	2024-07-04T05:11:16.707Z
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The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. 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Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome

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