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Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration

ABSTRACT: The type III RNase Dicer is responsible for the maturation and function of microRNA (miRNA) molecules in the cell. It is now well documented that Dicer and the fine-tuning of the miRNA gene network are important for neuronal integrity. However, the underlying mechanisms involved in neuronal death, particularly in the adult brain, remain poorly defined. Here, we show that absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. While neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further demonstrate that miRNAs belonging to the miR-15 family are potent regulators of ERK1 expression in mouse neuronal cells and co-expressed with ERK1/2 in vivo. Last, we show that miR-15a is specifically downregulated in Alzheimer’s disease brain. In sum, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation. Dicer KO vs. control

ORGANISM(S): Mus musculus

SUBMITTER: Ezequiel Calvo

PROVIDER: E-GEOD-23847 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration

Project description:The type III RNase Dicer is responsible for the maturation and function of microRNA (miRNA) molecules in the cell. It is now well documented that Dicer and the fine-tuning of the miRNA gene network are important for neuronal integrity. However, the underlying mechanisms involved in neuronal death, particularly in the adult brain, remain poorly defined. Here, we show that absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. While neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further demonstrate that miRNAs belonging to the miR-15 family are potent regulators of ERK1 expression in mouse neuronal cells and co-expressed with ERK1/2 in vivo. Last, we show that miR-15a is specifically downregulated in Alzheimer’s disease brain. In sum, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation.

2010-08-28 | GSE23847 | GEO

Expression data from Panc1 pancreatic epithelial cells

Project description:KrÃ¼ppel-like factors (KLFs) are a group of master regulators of gene expression conserved from flies to human. However, scant information is available on either the mechanisms or functional impact of the coupling of KLF proteins to chromatin remodeling machines, a deterministic step in transcriptional regulation. In the current study, we use genome-wide analyses of chromatin immunoprecipitation (ChIP-on-Chip) and Affymetrix-based expression profiling to gain insight into how the KLF11, a human transcription factor involved in tumor suppression and metabolic diseases, works by coupling to three co-factor groups: the Sin3-histone deacetylase system, WD40-domain containing proteins, and the HP1-histone methyltransferase system. We utilized genome-wide expression analysis of wild type KLF11 and three mutants that disrupt KLF11-chromatin machinery interactions to examine the relationship of the transcription factor and chromatin systems in the regulation of gene networks. Panc1 epithelial cells were plated at a density of 1x10^6 cells/100mm dish and transduced with empty vector, KLF11, KLF11-A347S, KLF11-486, or KLF11-EAPP adenovirus at an MOI of 150. RNA was prepared as previously described from pooled biological triplicates.

2014-08-01 | E-GEOD-56778 | biostudies-arrayexpress

Gene Expression Profile of Androgen Modulated Genes in the Murine Fetal Developing Lung

Project description:Accumulating evidences suggest that sex affects lung development. During the fetal period, male lung maturation is delayed compared with female and surfactant production appears earlier in female than in male fetal lungs. We analyzed by microarrays the expression of genes showing a sexual difference and those modulated by endogenous androgens (flutamide). Following flutamide or vehicle administration to pregnant mothers, fetal mouse lungs were studied at gestational day 17 (GD17) and GD18. RNA was extracted and hybridized on Affymetrix microarrays.

2010-01-14 | E-GEOD-18135 | biostudies-arrayexpress

Gene expression data of C57BL/6, Il1a-knockout and Il1b-knockout mice at 24 hours after spinal cord injury

Project description:We have previously shown that Il1a-knockout (KO) mice exhibit rapid (at day 1) and persistent improvements in locomotion associated with reduced lesion volume compared with Il1b-KO mice and C57BL/6 controls after traumatic spinal cord injury (SCI). To investigate the mechanism by which Il1a mediates its detrimental effect, we analyzed the transcriptome of the injured spinal cord of Il1a-KO, Il1b-KO and C57BL/6 mice at 24 hours after SCI using GeneChip microarrays. Il1a-KO, Il1b-KO and C57BL/6 mice were subjected to a 50-kdyn SCI and a 6-mm spinal cord segment centered over the site of contusion extracted for RNA isolation and microarray analysis.

2015-06-27 | E-GEOD-70302 | biostudies-arrayexpress

RNA sequencing of Tau overexpressing human SH-SY5Y cell line revels that Tau protein is able to alter global gene expression and chromatin structure

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2024-11-11 | GSE239956 | GEO

Timecourse expression data from sciatic nerve distal stump of C57BL/6 and C57BL/6 OlaHsd-Wlds mice.

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2011-06-01 | E-GEOD-22291 | biostudies-arrayexpress

In Vivo Endothelial Cell Heterogeneity

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2013-07-15 | E-GEOD-47067 | biostudies-arrayexpress

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation [scRNA-seq]

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2024-04-08 | GSE255904 | GEO

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation [bulk RNA-seq]

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Gene expression analysis of directly converted brown adipocytes (dBAs). [mouse]

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2015-08-12 | E-GEOD-56634 | biostudies-arrayexpress

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