title: Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis.
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.
authors.affiliation: Department of Biology, University of Miami, Coral Gables, FL, USA, robkozol@bio.miami.edu jdallman@bio.miami.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kozol
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Holly N
authors.initials: HN
authors.lastname: Cukier
authors.affiliation: Department of Biology, University of Miami, Coral Gables, FL, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zou
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Mayo
authors.affiliation: Seaver Autism Center for Research and Treatment, Department of Psychiatry, Friedman Brain Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA and.
authors.forename: Silvia
authors.initials: S
authors.lastname: De Rubeis
authors.affiliation: Seaver Autism Center for Research and Treatment, Department of Psychiatry, Friedman Brain Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA and.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Griswold
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Patrice L
authors.initials: PL
authors.lastname: Whitehead
authors.affiliation: Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cuccaro
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.affiliation: Department of Biology, University of Miami, Coral Gables, FL, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Baker
authors.affiliation: Seaver Autism Center for Research and Treatment, Department of Psychiatry, Friedman Brain Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA and.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Department of Biology, University of Miami, Coral Gables, FL, USA, robkozol@bio.miami.edu jdallman@bio.miami.edu.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Dallman
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001921:Brain / Q000196:embryology*; D030541:Databases, Genetic; D047108:Embryonic Development; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D020440:Gene Duplication; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics*; D010641:Phenotype; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D009419:Nerve Tissue Proteins; C000607103:SHANK3 protein, zebrafish; C112202:Syngap1 protein, rat; D029961:Zebrafish Proteins; D020703:ras GTPase-Activating Proteins; C000607104:syngap1b protein, zebrafish