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Gene expression profiles of striatum and cerebellum from knock-in mouse model of Huntington's disease

ABSTRACT: Huntington’s disease (HD) involves marked early neurodegeneration in the striatum whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, we compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions. Importantly, the quantitatively different responses in striatum and cerebellum in mutant mice were well accounted for by the intrinsic molecular differences in gene expression between striatum and cerebellum in wild-type animals. Tissue-specific gene expression changes in response to the HD mutation, therefore, appear to reflect the different inherent capacities of these tissues to buffer qualitatively similar effects of mutant huntingtin. These findings highlight a role for intrinsic quantitative tissue differences in contributing to HD pathogenesis, and likely to other neurodegenerative disorders exhibiting tissue-specificity, thereby guiding the search for effective therapeutic interventions. Total RNA was isolated from striatum and cerebellum of Hdh CAG knock-in mice (HdhQ111/HdhQ111) and wild-type mice (Hdh+/Hdh+, 3~10 weeks) for gene expression profiling using Affymetrix MG430 2.0 arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Jong-Min Lee

PROVIDER: E-GEOD-9038 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression profiles of striatum and cerebellum from knock-in mouse model of Huntington's disease

Project description:Huntington’s disease (HD) involves marked early neurodegeneration in the striatum whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, we compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions. Importantly, the quantitatively different responses in striatum and cerebellum in mutant mice were well accounted for by the intrinsic molecular differences in gene expression between striatum and cerebellum in wild-type animals. Tissue-specific gene expression changes in response to the HD mutation, therefore, appear to reflect the different inherent capacities of these tissues to buffer qualitatively similar effects of mutant huntingtin. These findings highlight a role for intrinsic quantitative tissue differences in contributing to HD pathogenesis, and likely to other neurodegenerative disorders exhibiting tissue-specificity, thereby guiding the search for effective therapeutic interventions.

2011-08-23 | GSE9038 | GEO

Transcriptome profiling in knock-in mouse models of Huntington's disease [Striatum_miRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the striatum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2016-02-15 | E-GEOD-65773 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Striatum_mRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the striatum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2016-02-15 | E-GEOD-65774 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease (striatum_mRNA).

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 6 and 10 month old knock-in mice with CAG lengths of 20, 50, 92, 140 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on samples from the Corpus Striatum tissue of 6 and 10 month old knock-in mice with CAG lengths of 20, 50, 92, 140 along with littermate control wild-type animals.

2016-02-24 | E-GEOD-78274 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Striatum_miRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 6 and 10 months old knock-in mice with CAG lengths of 20, 50, 92, 140 along with littermate control wild-type animals miRNA expression profiles were obtained via RNA-seq analysis performed on samples from the Striatum tissue of 6 and 10 months old knock-in mice with CAG lengths of 20, 50, 92, 140 along with littermate control wild-type animals.

2016-03-01 | E-GEOD-78793 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Cerebellum_miRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals. miRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the cerebellum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2015-11-03 | E-GEOD-73505 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [cerebellum_mRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals mRNA expression profiles were obtained via RNA-seq analysis performed on tissue samples from the cerebellum of 2, 6, and 10 month old knock-in mice with CAG lengths of 20, 80, 92, 111, 140, 175 along with littermate control wild-type animals.

2015-11-03 | E-GEOD-73468 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [Cerebellum_miRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 6 and 10 months old knock-in mice with CAG lengths of 20, 50, 92, 140 along with littermate control wild-type animals miRNA expression profiles were obtained via RNA-seq analysis performed on samples from the Cerebellum tissue of 6 and 10 months old knock-in mice with CAG lengths of 20, 50, 92, 140 along with littermate control wild-type animals.

2016-03-01 | E-GEOD-78790 | biostudies-arrayexpress

Transcriptome profiling in knock-in mouse models of Huntington's disease [AllelicSeries_6month_TissueSurvey_mRNA]

Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric alterations. The mutation responsible for this disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin (Htt). Knock-in mouse models of HD with human exon 1 containing expanded CAG repeats inserted in the murine huntingtin gene (Hdh) provide a genetic reconstruction of the human causative mutation within the mouse model. The goal of this study is RNA expression profiling by RNA sequencing (RNA-seq) in 6 month old knock-in mice with CAG lengths of 175 along with littermate control wild-type animals. mRNA expression profiles were obtained via RNA-seq analysis performed on samples from the Brown Adipose tissue, White Adipose tissue around Gonad, White Adipose tissue around Intestine, Brain - Brainstem, Brain - Cerebellum, Brain - Hippocampus, Brain - Hypothalamus/Thalamus, Corpus callosum, Gastrocnemius, Heart, and Skin of 6 month old knock-in mice with CAG lengths of 175 along with littermate control wild-type animals.

2016-02-15 | E-GEOD-65775 | biostudies-arrayexpress

Microarray gene expression data from Hdh knock-out, wild-type and knock-in embryonic stem cells

Project description:Huntington's disease (HD) features a unique disease-initiating mechanism hypothesized to entail an impact of the CAG repeat encoded polyglutamine region on the full-length huntingtin protein, with dominant effects that are continuous with CAG size, in a simple gain of function. To evaluate these predictions, we generated a series of heterozygous Hdh CAG knock-in mouse embryonic stem (ES) cell lines, with 18, 48, 89, 109 CAGs, and found that a continuous analytic strategy efficiently identified, from genome-wide datasets, 73 genes and 172 pathways whose expression varied continuously with CAG length. The CAG-correlated genes were distinct from the set of 754 genes that distinguished huntingtin null ES cells from wild-type controls, and CAG-correlated pathways did not display a one-to-one correspondence with the 238 pathways altered in huntingtin null ES cells. Rather, the genes that varied with CAG size were either members of the same pathways as altered genes in huntingtin null cells or were members of unique pathways related to these pathways. These findings falsified a gain of function/loss of function proposal but were consistent with the simple gain of novel function mechanism hypothesis. The dominant CAG correlated gene expression changes conformed to the genetic features of the HD initiating mechanism and were system-wide and inter-related with pathways perturbed by lack of full-length huntingtin function, urging system-wide approaches for the discovery and validation of potential modulating factors, in the search for effective HD therapeutics. Undifferentiated mouse embryonic stem cells without Hdh or with knock-in alleles with different Hdh CAG repeat sizes were profiled by Affymetrix MG 430 2.0 arrays.

2011-05-04 | E-GEOD-26001 | biostudies-arrayexpress

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