A mouse mutation that dysregulates neighboring Galnt17 and Auts2 genes is associated with phenotypes related to the human AUTS2 syndrome
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ABSTRACT:
PROVIDER: PRJNA548753 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9291540.fastq.gz | Fastqsanger.gz | |||
| SRR9291550.fastq.gz | Fastqsanger.gz | |||
| SRR9291560.fastq.gz | Fastqsanger.gz | |||
| SRR9291541.fastq.gz | Fastqsanger.gz | |||
| SRR9291551.fastq.gz | Fastqsanger.gz |
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Project description:AUTS2 was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder (ASD), intellectual disability, and epilepsy. Since that initial finding, AUTS2-linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, suggesting that AUTS2 is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could also involve neighboring genes. Of particular interest in this regard is the nearest downstream neighbor of AUTS2, GALNT17, encoding a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse (Mus musculus) mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between Auts2 and Galnt17 and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human AUTS2-linked phenotypes very well. In addition to abnormalities in growth, craniofacial structure, learning and memory, and behavior, 16Gso homozygotes display distinct pathologies of the cerebellum and hippocampus that are similar to those associated with ASD and other types of neurological disease associated with this genomic region. Analyzing the mutant cerebellar and hippocampal transcriptomes, we identified disturbances in pathways related to neurite and synapse maturation, neurotransmitter signaling, and cellular stress, suggesting possible cellular mechanisms for 16Gso phenotypes. These pathways, coupled with the translocation’s selective effects on Auts2 isoforms and coordinated dysregulation of Galnt17, suggest novel hypotheses regarding the etiology of the human “AUTS2 syndrome” and the wide array of neurodevelopmental disorders linked to variance in this genomic region.
2019-10-18 | GSE132684 | GEO
Project description:AUTS2 was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder, intellectual disability, and epilepsy. Since that initial finding, AUTS2-linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, sugg esting that AUTS2 is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could also involve neighboring genes. Of particular interest is the nearest downstream neighbor of AUTS2, GALNT17, which encodes a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse (Mus musculus) mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between Auts2 and Galnt17 and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human AUTS2-linked phenotypes very well. In addition to abnormalities in growth, craniofacial structure, learning and memory, and behavior, 16Gso homozygotes display distinct pathologies of the cerebellum and hippocampus that are similar to those associated with autism and other types of AUTS2-linked neurological disease. Analyzing mutant cerebellar and hippocampal transcriptomes to explain this pathology, we identified disturbances in pathways related to neuron and synapse maturation, neurotransmitter signaling, and cellular stress, suggesting possible cellular mechanisms. These pathways, coupled with the translocation's selective effects on Auts2 isoforms and coordinated dysregulation of Galnt17, suggest novel hypotheses regarding the etiology of the human "AUTS2 syndrome" and the wide array of neurodevelopmental disorders linked to variance in this genomic region.
| S-EPMC6829118 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE36950: SNP array for CNV calling AUTS2 project [Affymetrix] GSE37141: Oligo array for CNV calling AUTS2 project [Agilent] GSE37142: SNP array for CNV calling AUTS2 project [Illumina] GSE37654: Oligo array for calling CNV's for AUTS2 project [NimbleGen] GSE37656: Oligo array for CNV calling AUTS2 project [Bluegnome] Refer to individual Series
2012-07-11 | E-GEOD-37657 | biostudies-arrayexpress
Project description:Individuals with disruptions in the Autism Susceptibility Candidate 2 (AUTS2) gene frequently exhibit symptoms like intellectual disability, microcephaly, growth retardation, and distinct skeletal and facial differences. The role of AUTS2 in neurodevelopment has been explored using animal models and in vitro embryonic stem cell models. However, the precise molecular mechanisms through which AUTS2 influences neurodevelopment, particularly in humans, are not thoroughly understood. To address this, our study employs a 3D human organoid culture system, in combination with genetic, genomic, cellular, and molecular approaches, to investigate how AUTS2 impacts neurodevelopment through cellular signaling pathways. We used CRISPR/Cas9 technology to create AUTS2-deficient human embryonic stem cells (hESCs), replicating a 190kb genetic deletion observed in a patient. These cells were then differentiated into cerebral organoids. Our single-cell RNA sequencing (scRNA-seq) analysis of these organoids indicates that the absence of AUTS2 results in a significant reduction in neuron-related cells and an increase in choroid plexus (ChP) epithelial cells. Notably, our research reveals that AUTS2 negatively regulates the Wnt/β-catenin signaling pathway, evidenced by the observed overactivation of this pathway in AUTS2-deficient organoids as well as in a luciferase reporter cell line with AUTS2 deletion. Importantly, treating the AUTS2-deficient cerebral organoids with a Wnt inhibitor ameliorated the abnormalities in neuronal differentiation. This study offers new insights into the role of AUTS2 in neurodevelopment and suggests new potential targeted therapies for NDDs.
2024-09-27 | GSE255184 | GEO
Project description:Individuals with disruptions in the Autism Susceptibility Candidate 2 (AUTS2) gene frequently exhibit symptoms like intellectual disability, microcephaly, growth retardation, and distinct skeletal and facial differences. The role of AUTS2 in neurodevelopment has been explored using animal models and in vitro embryonic stem cell models. However, the precise molecular mechanisms through which AUTS2 influences neurodevelopment, particularly in humans, are not thoroughly understood. To address this, our study employs a 3D human organoid culture system, in combination with genetic, genomic, cellular, and molecular approaches, to investigate how AUTS2 impacts neurodevelopment through cellular signaling pathways. We used CRISPR/Cas9 technology to create AUTS2-deficient human embryonic stem cells (hESCs), replicating a 190kb genetic deletion observed in a patient. These cells were then differentiated into cerebral organoids. Our single-cell RNA sequencing (scRNA-seq) analysis of these organoids indicates that the absence of AUTS2 results in a significant reduction in neuron-related cells and an increase in choroid plexus (ChP) epithelial cells. Notably, our research reveals that AUTS2 negatively regulates the Wnt/β-catenin signaling pathway, evidenced by the observed overactivation of this pathway in AUTS2-deficient organoids as well as in a luciferase reporter cell line with AUTS2 deletion. Importantly, treating the AUTS2-deficient cerebral organoids with a Wnt inhibitor ameliorated the abnormalities in neuronal differentiation. This study offers new insights into the role of AUTS2 in neurodevelopment and suggests new potential targeted therapies for NDDs.
2024-09-27 | GSE255183 | GEO
Project description:Rearrangements within the AUTS2 region are associated with a rare syndromic disorder with intellectual disability, developmental delay and behavioral abnormalities as core features. In addition, smaller regional variants are linked to wide range of neuropsychiatric disorders, underscoring the gene’s essential role in brain development. Like many essential neurodevelopmental genes, AUTS2 is large and complex, generating distinct long (AUTS2-l) and short (AUTS2-s) protein isoforms from alternative promoters. Although evidence suggests unique isoform functions, the contributions of each isoform to specific AUTS2-linked phenotypes have not been clearly resolved. Furthermore, Auts2 is widely expressed across the developing brain, but cell populations most central to disease presentation have not been determined. In this study, we focused on the specific roles of AUTS2-l in brain development, behavior, and postnatal brain gene expression, showing that brain-wide AUTS2-l ablation leads to specific subsets of the recessive pathologies associated with C-terminal mutations that disrupt both isoforms. We identify downstream genes that could explain expressed phenotypes including hundreds of putative direct AUTS2-l target genes. Furthermore, in contrast to C-terminal Auts2 mutations which lead to dominant hypoactivity, AUTS2-l loss-of-function is associated with dominant hyperactivity, a phenotype exhibited by many human patients. Finally, we show that AUTS2-l ablation in Calbindin 1-expressing cell lineages is sufficient to yield learning/memory deficits and hyperactivity with abnormal dentate gyrus granule cell maturation, but not other phenotypic effects. These data provide new clues to in vivo AUTS2-l functions and novel information relevant to genotype-phenotype correlations in the human AUTS2 region.
2023-09-29 | GSE231599 | GEO
Project description:Previous studies have revealed that AUTS2 regulates cytoskeletal organization as well as gene expression during prenatal brain development. Its involvement in controlling synapses, however, remains unclear. Here, we report the increased dendritic spine formation in Auts2 mutant mice as well as the primary cultured neurons from Auts2 mutant mice. To investigate the involvement of AUTS2 function in the regulation of gene expression, we performed transcriptome analysis. RNA-seq on total RNA from the hippocampal tissues of Emx1Cre/+;Auts2flox/flox homozygous conditional KO mice at P14 reveals changes in gene associated with brain development including synapse formation. These results suggest that AUTS2 regulates the expression of genes that are related to synapse formation/function, and some of which may be involved in spine number restriction. Aberrant expression of such synaptic genes may cause synaptic dysfunction in patients with AUTS2 mutations.
2020-06-17 | GSE134712 | GEO
Project description:Molecular functions of the intellectual disability syndrome gene AUTS2 remain uncertain. Two mechanisms of Auts2 function have been proposed. One study found that Auts2 modifies Polycomb repressive complex 1 (PRC1) to activate transcription of target neurodevelopmental genes by recruiting EP300, a histone acetyltransferase. A second study found that cytoplasmic AUTS2 regulates cytoskeletal assembly through PREX1 to promote neurite outgrowth and migration. To further investigate Auts2 functions, we screened for AUTS2 interactors in cerebral cortex, and profiled changes of transcript expression in the developing cortex of Auts2 conditional mutant mice. AUTS2 immunoprecipitation experiments identified interactions with proteins involved in pre-mRNA processing, and mRNAs, including those encoding EP300 and PREX1, both bound by AUTS2-containing complexes and dysregulated in Auts2 mutant cortex. We propose that AUTS2 interacts with an RNA-binding complex that directly targets transcripts encoding Auts2 effectors. This mechanism provides a unifying model that accounts for previously disparate hypotheses of AUTS2 functions.
2021-05-21 | GSE112792 | GEO
Project description:Naturally occurring variations of Polycomb Repressive Complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, Autism Susceptibility Candidate 2 (AUTS2). While AUTS2 is often disrupted in patients with neuronal disorders, the underlying mechanism is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 thwarts PRC1 repressive activity and AUTS2-mediated recruitment of P300 leads to gene activation. ChIP-seq of AUTS2 shows that it regulates neuronal gene expression through promoter association. Conditional CNS targeting of Auts2 in a mouse model leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.
2014-12-18 | GSE60410 | GEO
Project description:Naturally occurring variations of Polycomb Repressive Complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, Autism Susceptibility Candidate 2 (AUTS2). While AUTS2 is often disrupted in patients with neuronal disorders, the underlying mechanism is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 thwarts PRC1 repressive activity and AUTS2-mediated recruitment of P300 leads to gene activation. ChIP-seq of AUTS2 shows that it regulates neuronal gene expression through promoter association. Conditional CNS targeting of Auts2 in a mouse model leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.
2014-12-18 | GSE60409 | GEO