PUBLICATION
CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene setd5 Leads to Social Impairments in Zebrafish
- Authors
- Gabellini, C., Pucci, C., De Cesari, C., Martini, D., Di Lauro, C., Digregorio, M., Norton, W., Zippo, A., Sessa, A., Broccoli, V., Andreazzoli, M.
- ID
- ZDB-PUB-230109-11
- Date
- 2022
- Source
- International Journal of Molecular Sciences 24(1): (Journal)
- Registered Authors
- Andreazzoli, Massimiliano, Norton, Will
- Keywords
- autism, behavior, neurodevelopment, setd5, zebrafish
- MeSH Terms
-
- Animals
- Autism Spectrum Disorder*/genetics
- Autism Spectrum Disorder*/metabolism
- Brain/metabolism
- CRISPR-Cas Systems
- Humans
- Methyltransferases*/genetics
- Methyltransferases*/metabolism
- Social Behavior
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 36613611 Full text @ Int. J. Mol. Sci.
Citation
Gabellini, C., Pucci, C., De Cesari, C., Martini, D., Di Lauro, C., Digregorio, M., Norton, W., Zippo, A., Sessa, A., Broccoli, V., Andreazzoli, M. (2022) CRISPR/Cas9-Induced Inactivation of the Autism-Risk Gene setd5 Leads to Social Impairments in Zebrafish. International Journal of Molecular Sciences. 24(1):.
Abstract
Haploinsufficiency of the SETD5 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 SETD5 haploinsufficiency, we generated zebrafish setd5 mutants using the CRISPR/Cas9 technology and characterized their morphological, behavioral and molecular phenotypes. According to our observation that setd5 is expressed in adult zebrafish brain, including those areas controlling social behavior, we found that setd5 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 setd5 mutant fishes. The zebrafish setd5 mutants display ASD-like features and are a promising setd5 haploinsufficiency model for drug screening aimed at reversing the behavioral phenotypes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping