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Expression data from 6 day-old Atxn1L-/- and Atxn1-/- lung tissues

ABSTRACT: Although expansion of a polyglutamine tract in ATAXIN1 (ATXN1) causes Spinocerebellar ataxia type 1, the functions of wild-type ATXN1 and ATAXIN1-Like (ATXN1L) remain poorly understood. To gain insight into the function of these proteins, we generated and characterized Atxn1L-/- and Atxn1-/- ; Atxn1L-/- double mutant animals. We found that Atxn1L -/- mice have several developmental problems including hydrocephalus, omphalocoele and lung alveolarization defects. These phenotypes are more penetrant and severe in Atxn1-/- ; Atxn1L-/- mice, suggesting that Atxn1 and Atxn1L are functionally redundant. To unravel the molecular mechanism underlying the alveolarization defect in Atxn1-/- mice, we carried out microarray analyses using total lung RNA from WT, Atxn1-/- and Atxn1L-/- mice

ORGANISM(S): Mus musculus

PROVIDER: GSE29551 | GEO | 2011/11/06

SECONDARY ACCESSION(S): PRJNA141315

REPOSITORIES: GEO

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Expression data from 6 day-old Atxn1L-/- and Atxn1-/- lung tissues

Project description:Although expansion of a polyglutamine tract in ATAXIN1 (ATXN1) causes Spinocerebellar ataxia type 1, the functions of wild-type ATXN1 and ATAXIN1-Like (ATXN1L) remain poorly understood. To gain insight into the function of these proteins, we generated and characterized Atxn1L-/- and Atxn1-/- ; Atxn1L-/- double mutant animals. We found that Atxn1L -/- mice have several developmental problems including hydrocephalus, omphalocoele and lung alveolarization defects. These phenotypes are more penetrant and severe in Atxn1-/- ; Atxn1L-/- mice, suggesting that Atxn1 and Atxn1L are functionally redundant. To unravel the molecular mechanism underlying the alveolarization defect in Atxn1-/- mice, we carried out microarray analyses using total lung RNA from WT, Atxn1-/- and Atxn1L-/- mice Lung tissues were dissected from 6 day old mice from either Atxn1 heterozyous intercrosses or Atxn1L heterozygous intercrosses. We collected lung tissue samples from 4 pairs of WT and Atxn1-/- amd 3 pairs of WT and Atxn1-/- mice. Total RNA extracted from the samples was subjected to microarray analysis using Affymetrix mouse gene ST 1.0 array. GSM731591-GSM731598 (Atxn1L KO and controls) and GSM731599-GSM731604 (Atxn1 KO and controls) were RMA-processed separately.

2011-11-06 | E-GEOD-29551 | biostudies-arrayexpress

Therapeutic effects of ASO-mediated reduction of Atxn1 in a SCA1 Mouse Mode: Proof of concept with distinct disease-associated transcriptome profiles in cerebellum and medulla

Project description:RNA-targeting approaches have improved disease symptoms in preclinical rodent models of several neurological diseases. Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited ataxia caused by expansion of a polyglutamine tract in the encoded protein Ataxin-1 (ATXN1). Despite advances in understanding this CAG repeat/polyglutamine expansion disease, there are still no therapies to alter its progressive fatal course. Here we investigate the therapeutic capability of an antisense oligonucleotide (ASO) targeting mouse Atxn1 in Atxn 1 154Q/2Q knockin mice that manifest motor deficits and premature lethality. Following a single ASO treatment at 5 weeks of age, mice demonstrated rescue of these disease-associated phenotypes. In addition, RNA-seq on vehicle-treated Atxn1 154Q/2Q and ASO-treated Atxn1 154Q/2Q mice were used to demonstrate molecular differences between SCA1 pathogenesis in the cerebellum that underlies ataxia with disease in the medulla associated with lethality. Together, these findings support the efficacy and therapeutic importance of directly targeting ATXN1 expression as a strategy to rescue both motor deficits and lethality seen in SCA1.

2019-05-31 | GSE114674 | GEO

Reduction of Protein Kinase A-mediated Phosphorylation of ATXN1-S776 in Purkinje Cells Delays Onset of Ataxia in a SCA1 Mouse Model.

Project description:Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation. We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Cα in Pcp2-ATXN1[82Q] mice. Here we show that pharmacologic inhibition of S776 phosphorylation in transfected cells and SCA1 patient iPSC-derived neuronal cells lead to a decrease in ATXN1. In vivo, reduction of PKA-mediated ATXN1-pS776 results in enhanced degradation of ATXN1 and improved cerebellar-dependent motor performance. These results provide evidence that PKA is a biologically important kinase for ATXN1-pS776 in cerebellar Purkinje cells.

2019-05-31 | GSE114815 | GEO

Transcription profiling of ataxin-null (Atxn-null) vs. wild type mice to investigate spinocerebellar ataxia type 1 (SCA1)

Project description:Ataxin 1 (Atxn1) is a protein of unknown function associated with cerebellar neurodegeneration in spinocerebellar ataxia type 1 (SCA1). SCA1 is caused by an expanded polyglutamine within Atxn1 by gain-of-function mechanisms. Lack of Atxn1 in mice triggers motor deficits in the absence of neurodegeneration or apparent neuropathological abnormalities.We extracted RNA from cerebellum of 5 Atxn1-null mice and 5 WT. Cerebellar gene expression profiles at 15 weeks of age were generated usSCA1 ing Affymetrix MOE430A arrays. Identifying the molecular pathways regulated by Atxn1 can provide insights into the early molecular mechanisms underlying neuronal dysfunction.

2006-12-01 | E-MEXP-886 | biostudies-arrayexpress

Decreasing Mutant ATXN1 Nuclear Localization Improves a Spectrum of SCA1-Like Phenotypes and Brain Region Transcriptomic Profiles

Project description:Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes with expression corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum.

2022-12-01 | GSE218303 | GEO

Atxn1L is a novel regulator of Hematopoietic Stem Cell Quiescence

Project description:We compared gene expression differences in Atxn1L knockout vs wildtype HSCs KO allele described in Pub Med ID: 22014525 HSCs were purified as Lineage-negative, Sca-1+ c-Kit+ (LSK), CD150+ and Side population from both Atxn1L-null and WT mice on C57Bl/6 background

2013-02-28 | E-GEOD-44285 | biostudies-arrayexpress

CIC and ATXN1L knockout gene expression data [NHA]

Project description:CIC has recently been implicated as a negative prognostic factor in multiple cancers. CIC and ATXN1L have been reported as interactors in several cellular contexts including development and disease state. To investigate the relationship between CIC and ATXN1L on a transcriptomic level, CIC-KO and ATXN1L-KO cell lines were generated. Gene expression profiling of CIC-KO and ATXN1L-KO cell lines was performed by microarray and differentially expressed genes were compared. We found a high degree of overlap in differentially expressed genes in CIC-KO and ATXN1L-KO suggesting loss of either interacting partner to lead to similar transcriptomic changes.

2017-09-30 | GSE103514 | GEO

CIC and ATXN1L knockout gene expression data [HEK]

2017-09-30 | GSE103513 | GEO

Cerebellar RNA-Seq from ATXN1 Transgenic Mice Reveals SCA1 Disease Progression and Protection Pathways

Project description:SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA-seq to profile cerebellar RNA expression in ATXN1 mice, including lines with ataxia and progressive pathology and lines having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar RNA-seq data revealed two gene networks that significantly correlated with disease, the Magenta (342 genes) and Light Yellow (35 genes) Modules. Features of the Magenta and Light Yellow Modules indicate they reflect distinctive pathways. The Magenta Module provides a description of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects other transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. We also found that up-regulation of cholecystokinin (Cck) blocked progression of Purkinje cell pathology and that loss of Cck function in mice lacking progressive disease enabled Purkinje cell pathology to progress to cell death.

2016-04-25 | GSE75778 | GEO

Atxn1L is a novel regulator of Hematopoietic Stem Cell Quiescence

Project description:We compared gene expression differences in Atxn1L knockout vs wildtype HSCs KO allele described in Pub Med ID: 22014525

2013-02-28 | GSE44285 | GEO