Zebrafish knockout of Down syndrome gene, DYRK1A , shows social impairments relevant to autism

maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo KO model using zebrafish. We identified a patient with a mutation in the gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of KO zebrafish through in situ hybridization with various probes including and which are the molecular markers for stress response. Microarray detected an intragenic microdeletion of in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in KO zebrafish was further confirmed by molecular analysis of and expression. Transcriptional expression of and was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context. In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes.