PUBLICATION
Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis
- Authors
- Kozol, R.A., Cukier, H.N., Zou, B., Mayo, V., De Rubeis, S., Cai, G., Griswold, A.J., Whitehead, P.L., Haines, J.L., Gilbert, J.R., Cuccaro, M.L., Martin, E.R., Baker, J.D., Buxbaum, J.D., Pericak-Vance, M.A., Dallman, J.E.
- ID
- ZDB-PUB-150418-11
- Date
- 2015
- Source
- Human molecular genetics 24(14): 4006-23 (Journal)
- Registered Authors
- Dallman, Julia
- Keywords
- none
- MeSH Terms
-
- Organogenesis/genetics*
- Embryonic Development
- Gene Knockdown Techniques
- Brain/embryology*
- Databases, Genetic
- Phenotype
- Gene Duplication
- Haploinsufficiency
- Autism Spectrum Disorder/genetics*
- Gene Expression Regulation, Developmental
- ras GTPase-Activating Proteins/genetics*
- ras GTPase-Activating Proteins/metabolism
- Animals
- GTPase-Activating Proteins/genetics*
- GTPase-Activating Proteins/metabolism
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- Zebrafish/embryology
- Zebrafish/genetics*
- Nerve Tissue Proteins/genetics*
- Nerve Tissue Proteins/metabolism
- PubMed
- 25882707 Full text @ Hum. Mol. Genet.
Citation
Kozol, R.A., Cukier, H.N., Zou, B., Mayo, V., De Rubeis, S., Cai, G., Griswold, A.J., Whitehead, P.L., Haines, J.L., Gilbert, J.R., Cuccaro, M.L., Martin, E.R., Baker, J.D., Buxbaum, J.D., Pericak-Vance, M.A., Dallman, J.E. (2015) Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis. Human molecular genetics. 24(14):4006-23.
Abstract
Despite significant progress in the genetics of autism spectrum disorder (ASD), how genetic mutations translate to the behavioral changes characteristic of ASD remains largely unknown. ASD affects 1-2% of children and adults, and is characterized by deficits in verbal and non-verbal communication, and social interactions, as well as the presence of repetitive behaviors and/or stereotyped interests. ASD is clinically and etiologically heterogeneous, with a strong genetic component. Here, we present functional data from syngap1 and shank3 zebrafish loss-of-function models of ASD. SYNGAP1, a synaptic Ras GTPase activating protein, and SHANK3, a synaptic scaffolding protein, were chosen because of mounting evidence that haploinsufficiency in these genes is highly penetrant for ASD and intellectual disability (ID). Orthologs of both SYNGAP1 and SHANK3 are duplicated in the zebrafish genome and we find that all four transcripts (syngap1a, syngap1b, shank3a and shank3b) are expressed at the earliest stages of nervous system development with pronounced expression in the larval brain. Consistent with early expression of these genes, knockdown of syngap1b or shank3a cause common embryonic phenotypes including delayed mid- and hindbrain development, disruptions in motor behaviors that manifest as unproductive swim attempts, and spontaneous, seizure-like behaviors. Our findings indicate that both syngap1b and shank3a play novel roles in morphogenesis resulting in common brain and behavioral phenotypes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping