Effect of the autism‐associated lncRNA Shank2‐AS on architecture and growth of neurons

Luo, Ting; Liu, Ping; Wang, Xiaoyan; Li, Le-Zhi; Zhao, Liping; Huang, Jin; Li, Yamin; Ou, Jin‐Lan; Peng, Xiaoqing

doi:10.1002/jcb.27471

Cited by 20 publications

(17 citation statements)

References 24 publications

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“…Unsuppressed elaboration of the dendritic tree in developing SHANK2 mutant neurons may increase the probability of establishing synaptic connections, leading to functional hyperconnectivity measured as strikingly increased sEPSC frequencies. It is possible that this mechanism applies broadly to ASD cases given the recent observation of increased abundance of SHANK2-AS long non-coding RNA and concurrently lowered SHANK2 protein levels in ASD samples without verified SHANK2 mutations 47 . As further ASD associated genes are shown to cause hyperconnectivity 48 , it will be important to determine how signalling pathways and common ASD enriched gene modules suppress or activate dendritic and synaptic regulation in excitatory neurons at both the transcriptional and translational levels.…”

Section: Discussionmentioning

confidence: 99%

SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons

et al. 2019

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Heterozygous loss-of-function mutations in SHANK2 are associated with autism spectrum disorder (ASD). We generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Spar se coculture for Con nectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed increases in dendrite length, dendrite complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 mutation. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in isogenic SHANK2 neurons was perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our findings provide evidence for hyperconnectivity and altered transcriptome in SHANK2 neurons derived from ASD subjects.

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Section: Discussionmentioning

confidence: 99%

SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons

et al. 2019

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“…In neurons, SHANK2-AS and Shank2 can form double-stranded RNA that inhibit the expression of Shank2 . Overexpression of SHANK2-AS reduces the complexity of neurites, and inhibits the proliferation of neuronal stem cells and promotes their apoptosis (Luo et al, 2018).…”

Section: Non-coding Rna In Neurodevelopmental Disordersmentioning

confidence: 99%

The Role of Non-Coding RNAs in Neurodevelopmental Disorders

2019

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Non-coding RNAs, a group of ribonucleic acids that are ubiquitous in the body and do not encode proteins, emerge as important regulatory factors in almost all biological processes in the brain. Extensive studies have suggested the involvement of non-coding RNAs in brain development and neurodevelopmental disorders, and dysregulation of non-coding RNAs is associated with abnormal brain development and the etiology of neurodevelopmental disorders. Here we provide an overview of the roles and working mechanisms of non-coding RNAs, and discuss potential clinical applications of non-coding RNAs as diagnostic and prognostic markers and as therapeutic targets in neurodevelopmental disorders.

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“…Most of the evidence, which characterized lncRNA dysregulation as an integral component of the transcriptomic signature of ASD, was derived from gene expression profiles of individuals with ASD (Ziats and Rennert, 2013;Wang et al, 2015;Gudenas et al, 2017). Only several lncRNAs associated with ASD have been identified by genome-derived evidence, and further explored in action mechanisms by loss-of-function or gain-of-function experiments, such as SHANK2-AS, MSNP1-AS, and BDNF-AS (DeWitt et al, 2016;Luo et al, 2018). In consideration of spatiotemporal-specific expression patterns, lncRNAs execute different functions and have unique gene expression patterns in distinct cellular conditions, therefore differentially expressed lncRNAs in a specific tissue could not reflect the global effects of dysregulated lncRNAs (Pramparo et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Identification and Functional Analysis of Long Non-coding RNAs in Autism Spectrum Disorders

2020

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Genetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, we first identified ASD-related lncRNAs based on genomic variant data of individuals with ASD from a twin study. In total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by an independent copy number variant (CNV) dataset. Then, the functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of their three different types of functional neighbor genes (i.e., genomic neighbors, competing endogenous RNA (ceRNA) neighbors, and gene co-expression neighbors in the cortex). The results have shown that most of the functional neighbor genes of ASD-related lncRNAs were enriched in nervous system development, inflammatory responses, and transcriptional regulation. Moreover, we explored the differential functions of ASD-related lncRNAs in distinct brain regions by using gene co-expression network analysis based on tissue-specific gene expression profiles. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. In addition, a functional network analysis was conducted for the highly reliable functional neighbor genes of ASD-related lncRNAs. We found that all the highly reliable functional neighbor genes were connected in a single functional network, which provided additional clues for the action mechanisms of ASD-related lncRNAs. Finally, we predicted several potential drugs based on the enrichment of drug-induced pathway sets in the ASD-altered biological pathway list. Among these drugs, several (e.g., amoxapine, piperine, and diflunisal) were partly supported by the previous reports. In conclusion, ASD-related lncRNAs participated in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. Detailed investigation into ASD-related lncRNAs can provide clues for developing potential ASD diagnosis biomarkers and therapy.

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Effect of the autism‐associated lncRNA Shank2‐AS on architecture and growth of neurons

Cited by 20 publications

References 24 publications

SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons

SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons

The Role of Non-Coding RNAs in Neurodevelopmental Disorders

Identification and Functional Analysis of Long Non-coding RNAs in Autism Spectrum Disorders

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