Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function

Guo, Daji; Peng, Yinghui; Wang, Laijian; Sun, Xiaoyu; Wang, Xiaojun; Liang, Chunmei; Yang, Xiaoman; Li, Shengnan; Xu, Junyu; Ye, Wen‐Cai; Jiang, Bin; Shi, Lei

doi:10.1038/s41380-019-0472-7

Cited by 72 publications

(74 citation statements)

References 65 publications

(80 reference statements)

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“…Findings in this study are consistent with the neurodevelopment impairment hypothesis of ASD and dyslexia, in which DOCK4 contributes to a shared genetic factor for both disorders. Using Dock4 knockout mice, we have shown that deficiency of Dock4 in vivo leads to social and communication deficits (Guo et al, 2019). Findings of the current study provide further molecular and cellular evidence that Dock4dependent regulation of neuronal development may underlie the neurobiology basis of social communication and language development.…”

Section: Discussionsupporting

confidence: 57%

“…Dock4 KO mice (C57BL/6 background) were generated using a standard strategy of Cre-LoxP recombination as previously described (Guo et al, 2019).…”

Section: Dock4 Ko Micementioning

confidence: 99%

“…Previous studies in both Dock4 KO mice and in Dock4-shRNA knockdown neurons have shown that Dock4 promotes dendritic spine formation and excitatory synaptic transmission in hippocampus (Ueda et al, 2013;Guo et al, 2019). To investigate the abilities of Dock4-R853H and 945VS on spine morphogenesis, we delivered each plasmid into cultured hippocampal neurons by calcium phosphate transfection at 9 DIV, and the co-expressed GFP was used to indicate morphology of the transfected neurons.…”

Section: Dock4-r853h and 945vs Have Compromised Abilities To Promote mentioning

confidence: 99%

“…Among them, Dock4 has attracted recent attention as emerging evidence suggests DOCK4 as a candidate gene for several neuropsychiatric diseases, including autism spectrum disorder (ASD), dyslexia and schizophrenia (Maestrini et al, 2010;Pagnamenta et al, 2010;Poelmans et al, 2011;Alkelai et al, 2012;Iossifov et al, 2014;Liang et al, 2014;Toma et al, 2014;Warrier et al, 2015;Shao et al, 2016;Lim et al, 2017;Akahoshi and Yamamoto, 2018;Kushima et al, 2018). Our previous study using Dock4 knockout mice have revealed that Dock4 deficiency in vivo leads to autism-like behaviors, including defects in social novelty preference and communication (Guo et al, 2019). In particular, impairment of Dock4-dependent excitatory synapse transmission in hippocampal CA1 pyramidal neurons is a main cause for the social deficits (Guo et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Our previous study using Dock4 knockout mice have revealed that Dock4 deficiency in vivo leads to autism-like behaviors, including defects in social novelty preference and communication (Guo et al, 2019). In particular, impairment of Dock4-dependent excitatory synapse transmission in hippocampal CA1 pyramidal neurons is a main cause for the social deficits (Guo et al, 2019). Moreover, Dock4 is suggested to play important roles in neuronal development such as axon guidance, dendrite development and dendritic spine morphogenesis (Ueda et al, 2008(Ueda et al, , 2013Xiao et al, 2013;Makihara et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development

Huang

Liang

et al. 2020

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both disorders have strong genetic basis, and share similar social communication deficits co-occurring with impairments of reading or language. However, whether these two disorders share common genetic risks remain elusive. DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. Dock4 is important for neuronal development and social behaviors. Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties. The present study explores the molecular and cellular functions of these two DOCK4 variants on neuronal development, by comparing them with the wild-type Dock4 protein. Notably, it is revealed that both mutants of Dock4 showed decreased ability to activate not only Rac1, but also another small GTPase Rap1. Consistently, both mutants were dysfunctional for regulation of cell morphology and cytoskeleton. Using Neuro-2a cells and hippocampus neurons as models, we found that both mutants had compromised function in promoting neurite outgrowth and dendritic spine formation. Electrophysiological recordings further showed that R853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability. Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.

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Section: Discussionsupporting

confidence: 57%

“…Dock4 KO mice (C57BL/6 background) were generated using a standard strategy of Cre-LoxP recombination as previously described (Guo et al, 2019).…”

Section: Dock4 Ko Micementioning

confidence: 99%

Section: Dock4-r853h and 945vs Have Compromised Abilities To Promote mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development

Huang

Liang

et al. 2020

Front. Cell. Neurosci.

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Magnetically Manipulated Optoelectronic Hybrid Microrobots for Optically Targeted Non‐Genetic Neuromodulation

Gao,

Guo,

Yang

et al. 2023

Advanced Materials

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Optically controlled neuromodulation is a promising approach for basic research of neural circuits and the clinical treatment of neurological diseases. However, developing a non‐invasive and well‐controllable system to deliver accurate and effective neural stimulation is challenging. Micro/nanorobots have shown great potential in various biomedical applications because of their precise controllability. Here, we present a magnetically manipulated optoelectronic hybrid microrobot (MOHR) for optically targeted non‐genetic neuromodulation. By integrating the magnetic component into the metal‐insulator‐semiconductor (MIS) junction design, the MOHR had excellent magnetic controllability and optoelectronic properties. The MOHR displayed a variety of magnetic manipulation modes that enabled precise and efficient navigation in different biofluids. Furthermore, the MOHR could achieve precision neuromodulation at the single‐cell level because of its accurate targeting ability. This neuromodulation was achieved by the MOHR's photoelectric response to visible light irradiation, which enhanced the excitability of the targeted cells. Finally, we showed that the well‐controllable MOHRs effectively restored neuronal activity in neurons damaged by β‐amyloid, a pathogenic agent of Alzheimer's disease. By coupling precise controllability with efficient optoelectronic properties, the hybrid microrobot system is a promising strategy for targeted on‐demand optical neuromodulation.This article is protected by copyright. All rights reserved

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Knockout of tanc2 causes autism‐like behavior and sleep disturbance in zebrafish

et al. 2022

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Tanc2 is a large multi‐domain postsynaptic scaffold protein mainly expressed in the brain. In humans, tanc2 mutations have been associated with autism spectrum disorder (ASD) and other related neurodevelopmental disorders. However, the role of tanc2 in neurodevelopment and in controlling behaviors are not fully understood. Here, we generated and characterized a tanc2 knockout allele in zebrafish. Loss of tanc2 increases the larval brain size and body length by promoting proliferation and inhibiting apoptosis. We observed that the glutamatergic neuron population is significantly increased in tanc2 mutants while the GABAergic and the glycinergic neurons are not affected, suggesting that an excitatory/inhibitory (E/I) imbalance. Indeed, the tanc2 knockout larvae exhibited increase sleep. In adult zebrafish, the mutants display anxiolytic‐behavior, reduced aggression, and impaired social preference. The alterations in these behaviors are phenotypically similar to the ASD patients carrying tanc2 mutations. Therefore, the tanc2 knockout allele could serve as a valuable model to further study the role of tanc2 in the nervous system.

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Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function

Cited by 72 publications

References 65 publications

Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development

Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development

Magnetically Manipulated Optoelectronic Hybrid Microrobots for Optically Targeted Non‐Genetic Neuromodulation

Knockout of tanc2 causes autism‐like behavior and sleep disturbance in zebrafish

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