Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development
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ABSTRACT:
PROVIDER: PRJNA716692 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14055052.fastq.gz | Fastqsanger.gz | |||
| SRR14055053.fastq.gz | Fastqsanger.gz | |||
| SRR14055054.fastq.gz | Fastqsanger.gz | |||
| SRR14055055.fastq.gz | Fastqsanger.gz |
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Project description:Background - One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B (ARID1B), a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. Methods - A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioural and tran¬scriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones delays. Results – We validated decreased Arid1b mRNA and protein in Arid1b+/- mice, with signatures of increased axonal and synaptic gene expression and decreased transcriptional regulator and RNA processing expression in adult Arid1b+/- cerebellum. During neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, as adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume in mice. Limitations – The behaviour and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioural findings, and the transcriptomic analyses was exploratory, with no validation of altered expression beyond Arid1b. Conclusions – This study represents a full validation and investigation of a novel model of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.
2021-03-24 | GSE169491 | GEO
Project description:BackgroundOne of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs.MethodsA novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays.ResultsWe validated decreased Arid1b mRNA and protein in Arid1b+/- mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b+/- cerebellum. During neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans.LimitationsThe behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b.ConclusionsThis study represents a full validation and investigation of a novel model of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.
| S-EPMC7986278 | biostudies-literature
Project description:There is growing evidence for the involvement of ARID1B, a SWI/SNF ATP-dependent chromatin remodeling subunit, in a broad range of human disorders. Sequencing studies have recurrently implicated ARID1B haploinsufficiency in autism spectrum disorder (ASD), non-syndromic intellectual disability (ID), corpus callosum agenesis, and short stature. In addition, ARID1B is by far the most common cause of Coffin-Siris Syndrome (CSS), a monogenic developmental delay syndrome characterized by a combination of the neuropsychiatric and physical abnormalities mentioned above. To understand how ARID1B mutations lead to these phenotypes, we generated Arid1b mutant mice, which exhibited physical manifestations of developmental delay and behaviors reminiscent of ASD. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF- regulated genes implicated in ASD.
2017-06-26 | GSE92238 | GEO
Project description:ARID1B KO in liver leads to minimal gene expression changes, whereas ARID1A/1B DKO leads to global gene expression changes.
2020-06-10 | GSE147664 | GEO
Project description:Arid1b is a chromatin remodeler implicated in neurodevelopmental disorders. Arid1b mutant mice with haploinsufficiency (Arid1b HT) displayed persistent excitatory synaptic dysfunction from juvenile to adult stage, decreased synaptic density and transmission. Moreover, they showed autistic-like behaviors in both of early and adult stages, decreased sociability in pup USV calling and adult social interaction, and adult repetitive grooming. To investigate early transcriptomic changes in Arid1b mutant mice, RNAseq analysis of prefrontal cortex from wild-type and Arid1b mutant mice at postnatal day 10 was done. Transcriptomic changes support these electrophysiological and behavioral deficits. Arid1b HT mice at postnatal day 10 showed alterations in genes implicated in synaptic functions and ASD.
2022-07-21 | GSE203249 | GEO
Project description:Arid1b is a chromatin remodeler implicated in neurodevelopmental disorders. Arid1b mutant mice with haploinsufficiency (Arid1b HT) displayed persistent excitatory synaptic dysfunction from juvenile to adult stage, decreased synaptic density and transmission. Moreover, they showed autistic-like behaviors in both of early and adult stages, decreased sociability in pup USV calling and adult social interaction, and adult repetitive grooming. To investigate pup stage transcriptomic changes in Arid1b mutant mice, RNAseq analysis of whole brain from wild-type and Arid1b mutant mice at postnatal day 3 was done. Transcriptomic changes support these electrophysiological and behavioral deficits. Arid1b HT mice at postnatal day 3 showed alterations in genes implicated in synaptic functions and ASD.
2022-07-21 | GSE203214 | GEO
Project description:Arid1b is a chromatin remodeler implicated in neurodevelopmental disorders. Arid1b mutant mice with haploinsufficiency (Arid1b HT) displayed persistent excitatory synaptic dysfunction from juvenile to adult stage, decreased synaptic density and transmission. Moreover, they showed autistic-like behaviors in both of early and adult stages, decreased sociability in pup USV calling and adult social interaction, and adult repetitive grooming. We found that early chronic fluoxetine treatment could carry out long-lasting restoration in electrophysiological and behavioral deficits in Arid1b HT mice. Prefrontal cortex specific transcriptomic analysis with mice at postnatal day 120 which underwent chronic fluoxetine treatment from postnatal day 3 to postnatal day 21 via mammillary milk was done to investigate transcriptomic reprogramming which contributes to this restoration.
2022-07-21 | GSE203343 | GEO
Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.
2021-10-12 | PXD028557 | Pride
Project description:Arid1b is a chromatin remodeler implicated in neurodevelopmental disorders. Arid1b mutant mice with haploinsufficiency (Arid1b HT) displayed persistent excitatory synaptic dysfunction from juvenile to adult stage, decreased synaptic density and transmission. Moreover, they showed autistic-like behaviors in both of early and adult stages, decreased sociability in pup USV calling and adult social interaction, and adult repetitive grooming. To investigate early transcriptomic changes in Arid1b mutant mice, RNAseq analysis of whole brain from wild-type and Arid1b mutant mice at postnatal day 10 was done. Transcriptomic changes support these electrophysiological and behavioral deficits. Arid1b HT mice at postnatal day 10 showed alterations in genes implicated in synaptic functions and ASD. Next, we found that early chronic fluoxetine treatment could carry out long-lasting restoration in electrophysiological and behavioral deficits in Arid1b HT mice. Whole brain transcriptomic analysis with mice at postnatal day 120 which underwent chronic fluoxetine treatment from postnatal day 3 to postnatal day 21 via mammillary milk was done to figure out transcriptomic reprogramming which contributes to this restoration. Comparing fluoxetine treated Arid1b HT mice and vehicle group, fluoxetine treated mice showed upregulation of synapse-related genes and disease related gene sets with reverse-ASD directions.
2022-07-21 | GSE189653 | GEO