High-throughput Functional Analysis of Autism Genes in Zebrafish Identifies Convergence in Dopaminergic and Neuroimmune Pathways
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA846486 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19560554_1.fastq.gz | Fastqsanger.gz | |||
| SRR19560554_2.fastq.gz | Fastqsanger.gz | |||
| SRR19560555_1.fastq.gz | Fastqsanger.gz | |||
| SRR19560555_2.fastq.gz | Fastqsanger.gz | |||
| SRR19560556_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 38 |
Similar Datasets
Project description:Investigation of convergence and divergence of different Autism Risk genes at the molecular level, in the brain of zebrafish ASD mutants at 6 days-post-fertilizitation (dpf)
2023-03-17 | GSE205578 | GEO
Project description:Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.
| S-EPMC10277173 | biostudies-literature
Project description:One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. To possibly circumvent this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin which regulate aspects of social behavior in mammals. However, whether genetic risk factors might predispose to autism due to modification of oxytocinergic signaling remains largely unknown. Here, we report that an autism-associated mutation in the synaptic adhesion molecule neuroligin-3 (Nlgn3) results in impaired oxytocin signaling in dopaminergic neurons and in altered social novelty responses in mice. Surprisingly, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3KO mice with a novel, highly specific, brain-penetrant inhibitor of MAP-kinase interacting kinases resets mRNA translation and restores oxytocin and social novelty responses. Thus, this work identifies an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, and oxytocinergic signaling. Focus on such common core plasticity elements might provide a pragmatic approach to reduce the heterogeneity of autism phenotypes. Ultimately, this would allow for mechanism-based stratification of patient populations to increase the success of therapeutic interventions.
2020-04-27 | PXD018808 | Pride
Project description:Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). Here, we show that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like behaviors, including autism-related behaviors, as well as deficits in cortical excitatory synaptic transmission. We find that hundreds of genes are dysregulated in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observe an enrichment of upregulated microglial genes, but not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduces a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduces social deficits and repetitive behavior. Together our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.
2020-10-24 | GSE139419 | GEO
Project description:We performed aCGH analysis using a custom Agilent oligonucleotide array to analyze 288 probands with idiopathic autism spectrum disorder (ASD) from the Simons Simplex Collection (SSC) of autism samples. The array is customized to high resolution coverage of exons for genes identified as encoding proteins included in a detailed protein interaction network for autism.
2011-06-08 | GSE29576 | GEO
Project description:Convergence of distinct RNA-silencing pathways on GW182/Tnrc6
| PRJNA848663 | ENA
Project description:Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
| S-EPMC4067558 | biostudies-literature
Project description:Convergence of distinct RNA-silencing pathways on GW182/Tnrc6 II
| PRJNA967370 | ENA
Project description:A causal role of mutations in genes encoding for multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations at the global level of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for global changes in the overall distribution of gene expression levels. For instance, in mice, we recently showed that variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in the variance in gene expression levels might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on purified RNA from peripheral blood lymphocytes of children with autism (n=82) and controls (n=64). The variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance in the overall distribution of gene expression levels. A decrease in the variance in the distribution of gene expression levels in peripheral blood lymphocytes (PBL) was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other neurodevelopmental disorders.
2011-10-09 | GSE25507 | GEO
Project description:The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.
2024-02-21 | GSE253063 | GEO