CRISPR-mediated activation of autism gene Itgb3 restores cortical network excitability via mGluR5 signaling

Jaudon, Fanny; Thalhammer, Agnes; Zentilin, Lorena; Cingolani, Lorenzo A.

doi:10.1016/j.omtn.2022.07.013

Cited by 13 publications

(4 citation statements)

References 95 publications

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“…The pLenti-U6-(BsmBI)-hSyn-SaCas9-P2A-EGFP vector allowing the expression of Staphylococcus aureus Cas9 and a gRNA for the knockdown of AP4β and AP4ε were constructed by replacing the EF-1α promoter in the pLenti_SaCRISPR-EGFP plasmid (gift from Christopher Vakoc; Addgene #118636) with the hSyn promoter from the pAAV-hSyn-EGFP plasmid (gift from Bryan Roth; Addgene #50465). The gRNA sequences were designed as previously described ( Jaudon et al, 2020 ; Jaudon et al, 2022 ; Riccardi et al, 2022 ) and were inserted downstream of the U6 promoter using BsmbI cloning sites. EGFP expression was used for visualisation of the transduced neurons.…”

Section: Methodsmentioning

confidence: 99%

The tetraspanin TSPAN5 regulates AMPAR exocytosis by interacting with the AP4 complex

Moretto

Miozzo

Longatti

et al. 2023

eLife

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Intracellular trafficking of AMPA receptors is a tightly regulated process which involves several adaptor proteins, and is crucial for the activity of excitatory synapses both in basal conditions and during synaptic plasticity. We found that, in rat hippocampal neurons, an intracellular pool of the tetraspanin TSPAN5 promotes exocytosis of AMPA receptors without affecting their internalisation. TSPAN5 mediates this function by interacting with the adaptor protein complex AP4 and Stargazin and possibly using recycling endosomes as a delivery route. This work highlights TSPAN5 as a new adaptor regulating AMPA receptor trafficking.

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Section: Methodsmentioning

confidence: 99%

The tetraspanin TSPAN5 regulates AMPAR exocytosis by interacting with the AP4 complex

Moretto

Miozzo

Longatti

et al. 2023

eLife

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“…Functional genomic approaches to interrogate the functional consequences of perturbing ASD risk genes, such as those involving CRISPR-based genetic screens both in model organisms [ 94 , 95 ] and in human pluripotent stem cell-derived neurons [ 64 , 96 ] and brain organoids [ 97 , 98 ], will also accelerate research progress in ASD. CRISPR-mediated gene therapy, such as CRISPR activation (CRISPRa) to recover the haploinsufficiency of ASD risk genes, has recently been used in preclinical studies [ 99 , 100 ] and holds great promise for the future of ASD treatment. Sophisticated computational approaches such as machine learning have the potential to predict risk genes using human brain-specific spatiotemporal gene expression signatures and protein–protein interaction networks, thus anticipating the trajectory of gene discovery in ASD [ 101 , 102 , 103 , 104 ].…”

Section: Challenges and Future Directionsmentioning

confidence: 99%

The Importance of Large-Scale Genomic Studies to Unravel Genetic Risk Factors for Autism

Nóbrega,

Teles e Silva,

Yokota-Moreno

et al. 2024

IJMS

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Autism spectrum disorder (ASD) is a common and highly heritable neurodevelopmental disorder. During the last 15 years, advances in genomic technologies and the availability of increasingly large patient cohorts have greatly expanded our knowledge of the genetic architecture of ASD and its neurobiological mechanisms. Over two hundred risk regions and genes carrying rare de novo and transmitted high-impact variants have been identified. Additionally, common variants with small individual effect size are also important, and a number of loci are now being uncovered. At the same time, these new insights have highlighted ongoing challenges. In this perspective article, we summarize developments in ASD genetic research and address the enormous impact of large-scale genomic initiatives on ASD gene discovery.

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“…[83][84][85] It has recently been shown that ITGB3, the gene encoding the ECM receptor integrin β3, can interact with mGluR5 to regulate the functional expression of synaptic mGluR5 and directly affect neuronal excitability. 86 Neurotransmitter imbalances play an important role in cognitive deficits in schizophrenia, 87 and depression and anxiety are also associated with imbalances in central nervous system 5-HT levels. And there is a close link between integrin β and several of those neurotransmitters.…”

Section: Mainly Mediate Cell-cell and Cell-ecm Adhesionmentioning

confidence: 99%

“…In addition, metabotropic glutamate (mGlu) receptors have long been used as important therapeutic targets for schizophrenia 83 85 It has recently been shown that ITGB3, the gene encoding the ECM receptor integrin β3, can interact with mGluR5 to regulate the functional expression of synaptic mGluR5 and directly affect neuronal excitability 86 . Neurotransmitter imbalances play an important role in cognitive deficits in schizophrenia, 87 and depression and anxiety are also associated with imbalances in central nervous system 5-HT levels.…”

Section: Integrin β Associated With Neurotransmitters In Schizophreniamentioning

confidence: 99%

The role of integrin beta in schizophrenia: a preliminary exploration

He¹,

Wang²,

Li³

et al. 2022

CNS Spectr.

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Integrins are transmembrane heterodimeric (αβ) receptors that transduce mechanical signals between the extracellular milieu and the cell in a bidirectional manner. Extensive research has shown that the integrin beta (β) family is widely expressed in the brain and that they control various aspects of brain development and function. Schizophrenia is a relatively common neurological disorder of unknown etiology and has been found to be closely related to neurodevelopment and neurochemicals in neuropathological studies of schizophrenia. Here, we review literature from recent years that shows that schizophrenia involves multiple signaling pathways related to neuronal migration, axon guidance, cell adhesion, and actin cytoskeleton dynamics, and that dysregulation of these processes affects the normal function of neurons and synapses. In fact, alterations in integrin β structure, expression and signaling for neural circuits, cortex, and synapses are likely to be associated with schizophrenia. We explored several aspects of the possible association between integrin β and schizophrenia in an attempt to demonstrate the role of integrin β in schizophrenia, which may help to provide new insights into the study of the pathogenesis and treatment of schizophrenia.

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CRISPR-mediated activation of autism gene Itgb3 restores cortical network excitability via mGluR5 signaling

Cited by 13 publications

References 95 publications

The tetraspanin TSPAN5 regulates AMPAR exocytosis by interacting with the AP4 complex

The tetraspanin TSPAN5 regulates AMPAR exocytosis by interacting with the AP4 complex

The Importance of Large-Scale Genomic Studies to Unravel Genetic Risk Factors for Autism

The role of integrin beta in schizophrenia: a preliminary exploration

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