CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene <i>setd5</i> Leads to Social Impairments in Zebrafish
Haploinsufficiency of the <i>SETD5</i> gene, encoding a SET domain-containing histone methyltransferase, has been identified as a cause of intellectual disability and Autism Spectrum Disorder (ASD). Recently, the zebrafish has emerged as a valuable model to study neurodevelopmental disor...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/1/167 |
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| author | Chiara Gabellini Cecilia Pucci Chiara De Cesari Davide Martini Caterina Di Lauro Matteo Digregorio William Norton Alessio Zippo Alessandro Sessa Vania Broccoli Massimiliano Andreazzoli |
| author_facet | Chiara Gabellini Cecilia Pucci Chiara De Cesari Davide Martini Caterina Di Lauro Matteo Digregorio William Norton Alessio Zippo Alessandro Sessa Vania Broccoli Massimiliano Andreazzoli |
| author_sort | Chiara Gabellini |
| collection | DOAJ |
| description | Haploinsufficiency of the <i>SETD5</i> gene, encoding a SET domain-containing histone methyltransferase, has been identified as a cause of intellectual disability and Autism Spectrum Disorder (ASD). Recently, the zebrafish has emerged as a valuable model to study neurodevelopmental disorders because of its genetic tractability, robust behavioral traits and amenability to high-throughput drug screening. To model human <i>SETD5</i> haploinsufficiency, we generated zebrafish <i>setd5</i> mutants using the CRISPR/Cas9 technology and characterized their morphological, behavioral and molecular phenotypes. According to our observation that <i>setd5</i> is expressed in adult zebrafish brain, including those areas controlling social behavior, we found that <i>setd5</i> heterozygous mutants exhibit defective aggregation and coordination abilities required for shoaling interactions, as well as indifference to social stimuli. Interestingly, impairment in social interest is rescued by risperidone, an antipsychotic drug used to treat behavioral traits in ASD individuals. The molecular analysis underscored the downregulation of genes encoding proteins involved in the synaptic structure and function in the adult brain, thus suggesting that brain hypo-connectivity could be responsible for the social impairments of <i>setd5</i> mutant fishes. The zebrafish <i>setd5</i> mutants display ASD-like features and are a promising <i>setd5</i> haploinsufficiency model for drug screening aimed at reversing the behavioral phenotypes. |
| first_indexed | 2024-03-11T09:59:47Z |
| format | Article |
| id | doaj.art-5a080da48fef40eb870b24c29032352e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:59:47Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5a080da48fef40eb870b24c29032352e2023-11-16T15:30:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124116710.3390/ijms24010167CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene <i>setd5</i> Leads to Social Impairments in ZebrafishChiara Gabellini0Cecilia Pucci1Chiara De Cesari2Davide Martini3Caterina Di Lauro4Matteo Digregorio5William Norton6Alessio Zippo7Alessandro Sessa8Vania Broccoli9Massimiliano Andreazzoli10Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56123 Pisa, ItalyUnit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56123 Pisa, ItalyUnit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56123 Pisa, ItalyUnit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56123 Pisa, ItalyUnit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56123 Pisa, ItalyUnit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56123 Pisa, ItalyDepartment of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UKLaboratory of Chromatin Biology & Epigenetics, Center for Integrative Biology (CIBIO), University of Trento, 38123 Trento, ItalyStem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, ItalyStem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, ItalyUnit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56123 Pisa, ItalyHaploinsufficiency of the <i>SETD5</i> gene, encoding a SET domain-containing histone methyltransferase, has been identified as a cause of intellectual disability and Autism Spectrum Disorder (ASD). Recently, the zebrafish has emerged as a valuable model to study neurodevelopmental disorders because of its genetic tractability, robust behavioral traits and amenability to high-throughput drug screening. To model human <i>SETD5</i> haploinsufficiency, we generated zebrafish <i>setd5</i> mutants using the CRISPR/Cas9 technology and characterized their morphological, behavioral and molecular phenotypes. According to our observation that <i>setd5</i> is expressed in adult zebrafish brain, including those areas controlling social behavior, we found that <i>setd5</i> heterozygous mutants exhibit defective aggregation and coordination abilities required for shoaling interactions, as well as indifference to social stimuli. Interestingly, impairment in social interest is rescued by risperidone, an antipsychotic drug used to treat behavioral traits in ASD individuals. The molecular analysis underscored the downregulation of genes encoding proteins involved in the synaptic structure and function in the adult brain, thus suggesting that brain hypo-connectivity could be responsible for the social impairments of <i>setd5</i> mutant fishes. The zebrafish <i>setd5</i> mutants display ASD-like features and are a promising <i>setd5</i> haploinsufficiency model for drug screening aimed at reversing the behavioral phenotypes.https://www.mdpi.com/1422-0067/24/1/167<i>setd5</i>zebrafishautismneurodevelopmentbehavior |
| spellingShingle | Chiara Gabellini Cecilia Pucci Chiara De Cesari Davide Martini Caterina Di Lauro Matteo Digregorio William Norton Alessio Zippo Alessandro Sessa Vania Broccoli Massimiliano Andreazzoli CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene <i>setd5</i> Leads to Social Impairments in Zebrafish International Journal of Molecular Sciences <i>setd5</i> zebrafish autism neurodevelopment behavior |
| title | CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene <i>setd5</i> Leads to Social Impairments in Zebrafish |
| title_full | CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene <i>setd5</i> Leads to Social Impairments in Zebrafish |
| title_fullStr | CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene <i>setd5</i> Leads to Social Impairments in Zebrafish |
| title_full_unstemmed | CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene <i>setd5</i> Leads to Social Impairments in Zebrafish |
| title_short | CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene <i>setd5</i> Leads to Social Impairments in Zebrafish |
| title_sort | crispr cas9 induced inactivation of the autism risk gene i setd5 i leads to social impairments in zebrafish |
| topic | <i>setd5</i> zebrafish autism neurodevelopment behavior |
| url | https://www.mdpi.com/1422-0067/24/1/167 |
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