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Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE146457 | GEO | 2020/03/06

REPOSITORIES: GEO

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Deficiency of STING Signaling in Embryonic Cerebral Cortex Leads to Neurogenic Abnormalities and Autistic-Like Behaviors.

Project description:STING is known as a central adaptor for sensing cytosolic DNA sensing. Recent studies have provided evidence that STING response is divergent among different cell types. Here, this work demonstrates that STING controls neural progenitor cells (NPCs) by sensing DNA damage in NPCs. The deletion of STING reduces neuronal differentiation and increases proliferation of mouse and human NPCs. Furthermore, STINGcKO mice display autistic-like behaviors. In NPCs, STING specifically recruits IKK? and activates nuclear factor ?B (NF-?B) through phosphorylation. NF-?B binds to ALX4 promoter and triggers ALX4 transcription. In addition, tumor necrosis factor ?, an activator of NF-?B, can rescue some phenotypes caused by STING deletion in mice. Together, the findings show that STING signaling is essential for neuronal gene expression program and has profound consequences on brain function.

| S-EPMC7710002 | biostudies-literature

Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex [bulk RNA-seq]

Project description:Purpose: To gain futher insight into how STING regulates the proliferative of neural progenitors ,RNA-seq was used to analyze the genome-wide changes resulting from the cerebral cortices of E13 STING conditional knock out mice and littermate wild-type. Methods: Total RNA from E13 telencephalic tissue of wild-type(WT) and STINGf/f;Nestin-Cre mice was extracted. Specifically, Agilent 2100 Bioanalyze was used to quality controlled and quantified. then, total RNA was converted to cDNA and bound the library. RNA-sequencing analysis was used by the Illumina HiSeq 2500 platform in Annoroad Genomics Results: Approximately one thousand transcripts showed differential expression between the wild-type(WT) and STINGf/f;Nestin-Cre mice brain cortex, with a fold change ≥1.5 and p value <0.05.Geneontology analysis of the down or up-regulated genes showed obvious enrichment of biological processes related to brain development and cell fate commitment. These results reflected STING plays a role in cortex development. Conclusions: RNA-seq based transcriptome characterization would provide a overall understanding how STING gene contribute to brain cortical development.

2020-03-06 | GSE146455 | GEO

Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex [single-cell RNA-seq]

Project description:Purpose: To gain futher insight into how STING causes abnormal cortical development in mice ,single cell RNA-seq was used to analyze the cell type changes resulting from the cerebral cortices of P0 STING conditional knock out mice and littermate wild-type. Methods: Single cell isolation was prepared from P0 telencephalic tissue of wild-type(WT) and STINGf/f;Nestin-Cre mice. The fragmented cDNAs containing barcode and UMI sequences was built the library . Agilent 2100 Bioanalyze was used to quality controlled and quantified.Single cell RNA-sequencing analysis was used by the Illumina HiSeq 2500 platform in Annoroad Genomics Results: Clustering and labeling of these cells visualized on a t-SNE plot between the wild-type(WT) and STINGf/f;Nestin-Cre mice brain cortex Conclusions: Single cell RNA-seq data would provide a overall understanding of how STING gene influences cortical development in mice.

2020-03-06 | GSE146456 | GEO

Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex

Project description:Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex

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Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex [bulk RNA-seq]

Project description:Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex [bulk RNA-seq]

| PRJNA610609 | ENA

Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex [single-cell RNA-seq]

Project description:Deficiency of STING-signaling leads to neurogenic abnormalities and Autistic-Like Behaviors in the embryonic cortex [single-cell RNA-seq]

| PRJNA610608 | ENA

Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits.

Project description:Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8+/- mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in Chd8+/- animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.

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TCF20 dysfunction leads to cortical neurogenesis defects and autistic-like behaviors in mice

Project description:Recently, de novo mutations of transcription factor 20 (TCF20) were found in patients with autism by large-scale exome sequencing. However, how TCF20 modulates brain development and whether its dysfunction causes ASD remain unclear. Here, we show that TCF20 deficits impair neurogenesis in mouse. TCF20 deletion significantly reduces the number of neurons, which leads to abnormal brain functions. Furthermore, transcriptome analysis and ChIP-qPCR reveal that the DNA demethylation factor TDG is a downstream target gene of TCF20. As a nonspecific DNA demethylation factor, TDG potentially affects many genes. Combined TDG ChIP-seq and GO analysis of TCF20 RNA-Seq identifies T cell factor 4 (TCF-4) as a common target. TDG controls the DNA methylation level in the promoter area of TCF-4, affecting TCF-4 expression and modulating neural differentiation. Overexpression of TDG or TCF-4 rescues the deficient neurogenesis of TCF20 knockdown brains. Together, our data reveal that TCF20 is essential for neurogenesis and we suggest that defects in neurogenesis caused by TCF20 loss are associated with ASD.

| S-SCDT-EMBOR-2019-49239V1 | biostudies-other

Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice.

Project description:Autism spectrum disorder (ASD) is associated with a range of abnormalities pertaining to socialization, communication, repetitive behaviors, and restricted interests. Owing to its complexity, the etiology of ASD remains incompletely understood. The presynaptic G protein-coupled glutamate receptor metabotropic glutamate receptor 7 (mGluR7) is known to be essential for synaptic transmission and is also tightly linked with ASD incidence. Herein, we report that prefrontal cortex (PFC) mGluR7 protein levels were decreased in C57BL/6J mice exposed to valproic acid (VPA) and BTBR T+ Itpr3tf/J mice. The overexpression of mGluR7 in the PFC of these mice using a lentiviral vector was sufficient to reduce the severity of ASD-like behavioral patterns such that animals exhibited decreases in abnormal social interactions and communication, anxiety-like, and stereotyped/repetitive behaviors. Intriguingly, patch-clamp recordings revealed that the overexpression of mGluR7 suppressed neuronal excitability by inhibiting action potential discharge frequencies, together with enhanced action potential threshold and increased rheobase. These data offer a scientific basis for the additional study of mGluR7 as a promising therapeutic target in ASD and related neurodevelopmental disorders.

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