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Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans

ABSTRACT: We isolated RNAs from Otp-lineage cells in the mouse brain using translating ribosome affinity purification (TRAP) approach. We compared two groups of mice: Otp-cre; ROSAfsTRAP (control) and Otp-cre; Cicf/f; ROSAfsTRAP (conditional knockout). Following RNA isolation, RNAseq was performed and gene expression profiles were compared between controls and conditional knockouts.

ORGANISM(S): Mus musculus

PROVIDER: GSE83243 | GEO | 2017/01/31

SECONDARY ACCESSION(S): PRJNA325369

REPOSITORIES: GEO

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Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.

Project description:Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons. We also found that CIC activity in the hypothalamus and medial amygdala modulates social interactions. Informed by these neurobehavioral features in mouse mutants, we identified five individuals with de novo heterozygous truncating mutations in CIC who share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.

| S-EPMC5374026 | biostudies-literature

Effect of fasting and ketogenic diet on hippocampal astrocytes in vivo

Project description:To understand the transcriptional effect of fasting and feeding a ketogenic diet on mouse CNS astrocytes, we performed translating ribosomal affinity purification (TRAP) of mRNAs immunoprecipitated from hippocampus. TRAP mice express a ribosomal epitope tag upon Cre-induced recombination that can be immunoprecipitated following activation. We measured the abundance of actively translating mRNAs from a ribosomal pull-down that came from adult astrocyte (Aldh1l1-Cre)-specific TRAP mice that were subjected to one of three dietary conditions: four weeks of normal chow diet, four weeks of ketogenic diet (high-fat, low-carbohydrate)43, or an 18-hour fast. Immediately following the respective diets, forebrain and hippocampus was harvested from all groups, ribosomes were immunoprecipitated, and actively translating mRNAs in the ribosomes were purified.

2021-05-24 | GSE169625 | GEO

TRAP-seq of VMH Nr5a1 neurons

Project description:To identify transcripts enriched in ventomedial hypothalamus (VMH) neurons, we used translating affinity ribosome purification combined with RNA-seq (TRAP-seq) from Nr5a1-Cre mice.

2021-05-19 | GSE172206 | GEO

TRAP-seq of VMH Lepr neurons

Project description:To identify transcripts enriched in ventomedial hypothalamus (VMH) Lepr neurons, we used translating affinity ribosome purification combined with RNA-seq (TRAP-seq) from Lepr-Cre mice.

2021-05-19 | GSE172200 | GEO

Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1 [CUT&RUN]

Project description:Genome wide binding profiles of CIC and H3K27ac in CIC KO (Engrailed1-Cre;Cicfl/fl), wildtype, Atxn1_154Q/2Q (SCA1), and Atxn1_154Q[V5591A;S602D]/2Q (154Q AXH) in the cerebellum

2022-12-13 | GSE218301 | GEO

TRAP-seq of VMH Lepr∩Slc17a6 neurons

Project description:To identify transcripts enriched in ventomedial hypothalamus (VMH) neurons that contain both Lepr and Slc17a6, we used translating affinity ribosome purification combined with RNA-seq (TRAP-seq) from Lepr-Cre;Slc17a6-Flpo mice.

2021-05-19 | GSE172202 | GEO

Gene expression profiling of inputs to the mesolimbic dopamine circuit

Project description:PRV-Circuit-TRAP of DAT-cre mice injected with PRV-Introvert-GFP in the nucleus accumbens These studies identify important inputs to the mesolimbic dopamine pathway and further show that PRV circuit-directed translating ribosome affinity purification (PRV-Circuit-TRAP) can be broadly applied to identify molecularly defined neurons comprising complex, multisynaptic circuits.

2017-03-20 | GSE95234 | GEO

Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1.

Project description:Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it is caused by a mutation in a broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; however, the importance of this interaction in other vulnerable cells remains unknown. Here, we mutated the 154Q knockin allele of Atxn1154Q/2Q mice to prevent the ATXN1-CIC interaction globally. This normalized genome-wide CIC binding; however, it only partially corrected transcriptional and behavioral phenotypes, suggesting the involvement of additional factors in disease pathogenesis. Using unbiased proteomics, we identified three ATXN1-interacting transcription factors: RFX1, ZBTB5, and ZKSCAN1. We observed altered expression of RFX1 and ZKSCAN1 target genes in SCA1 mice and patient-derived iNeurons, highlighting their potential contributions to disease. Together, these data underscore the complexity of mechanisms driving cellular vulnerability in SCA1.

| S-EPMC9957872 | biostudies-literature

ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization.

Project description:Although expansion of CAG repeats in ATAXIN1 (ATXN1) causes Spinocerebellar ataxia type 1, the functions of ATXN1 and ATAXIN1-Like (ATXN1L) remain poorly understood. To investigate the function of these proteins, we generated and characterized Atxn1L(-/-) and Atxn1(-/-); Atxn1L(-/-) mice. Atxn1L(-/-) mice have hydrocephalus, omphalocele, and lung alveolarization defects. These phenotypes are more penetrant and severe in Atxn1(-/-); Atxn1L(-/-) mice, suggesting that ATXN1 and ATXN1L are functionally redundant. Upon pursuing the molecular mechanism, we discovered that several Matrix metalloproteinase (Mmp) genes are overexpressed and that the transcriptional repressor Capicua (CIC) is destabilized in Atxn1L(-/-) lungs. Consistent with this, Cic deficiency causes lung alveolarization defect. Loss of either ATXN1L or CIC derepresses Etv4, an activator for Mmp genes, thereby mediating MMP9 overexpression. These findings demonstrate a critical role of ATXN1/ATXN1L-CIC complexes in extracellular matrix (ECM) remodeling during development and their potential roles in pathogenesis of disorders affecting ECM remodeling.

| S-EPMC3253850 | biostudies-literature

Transcription profiling by high throughput sequencing of pancreatic islets from LKB1 and AMPK knockout mice

Project description:RNA-Seq was performed on pancreatic islets from four transgenic mouse strains affecting LKB1 and AMPK. A conditional LKB1 knockout strain was generated. Double conditional knockouts for AMPK alpha1 and AMPK alpha2 were also generated. These conditional strains were crossed with RIP-Cre (driven by rat insulin promoter) or Ins1-Cre mice to generate LKB1 knockout and AMPK double knockout strains.

2014-10-25 | E-MTAB-2791 | biostudies-arrayexpress

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