RRC ID 66147
Author Kozol RA, Cukier HN, Zou B, Mayo V, De Rubeis S, Cai G, Griswold AJ, Whitehead PL, Haines JL, Gilbert JR, Cuccaro ML, Martin ER, Baker JD, Buxbaum JD, Pericak-Vance MA, Dallman JE.
Title Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis.
Journal Hum Mol Genet
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.
Volume 24(14)
Pages 4006-23
Published 2015-7-15
DOI 10.1093/hmg/ddv138
PII ddv138
PMID 25882707
PMC PMC4476447
MeSH Animals Autism Spectrum Disorder / genetics* Brain / embryology* Databases, Genetic Embryonic Development GTPase-Activating Proteins / genetics* GTPase-Activating Proteins / metabolism Gene Duplication Gene Expression Regulation, Developmental Gene Knockdown Techniques Haploinsufficiency Nerve Tissue Proteins / genetics* Nerve Tissue Proteins / metabolism Organogenesis / genetics* Phenotype Zebrafish / embryology Zebrafish / genetics* Zebrafish Proteins / genetics* Zebrafish Proteins / metabolism ras GTPase-Activating Proteins / genetics* ras GTPase-Activating Proteins / metabolism
IF 5.101
Zebrafish vglut2:dsRed