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Molecular Autism
Published in: Molecular Autism 1/2017

Open Access 01-12-2017 | Research

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

Authors: Oc-Hee Kim, Hyun-Ju Cho, Enna Han, Ted Inpyo Hong, Krishan Ariyasiri, Jung-Hwa Choi, Kyu-Seok Hwang, Yun-Mi Jeong, Se-Yeol Yang, Kweon Yu, Doo-Sang Park, Hyun-Woo Oh, Erica E. Davis, Charles E. Schwartz, Jeong-Soo Lee, Hyung-Goo Kim, Cheol-Hee Kim

Published in: Molecular Autism | Issue 1/2017

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Abstract

Background

DYRK1A 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 Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish.

Methods

We identified a patient with a mutation in the DYRK1A gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a dyrk1aa 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 dyrk1aa KO zebrafish through in situ hybridization with various probes including c-fos and crh which are the molecular markers for stress response.

Results

Microarray detected an intragenic microdeletion of DYRK1A in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, dyrk1aa KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in dyrk1aa KO zebrafish was further confirmed by molecular analysis of c-fos and crh expression. Transcriptional expression of c-fos and crh was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context.

Conclusions

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 DYRK1A 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.
Appendix
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Metadata
Title
Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism
Authors
Oc-Hee Kim
Hyun-Ju Cho
Enna Han
Ted Inpyo Hong
Krishan Ariyasiri
Jung-Hwa Choi
Kyu-Seok Hwang
Yun-Mi Jeong
Se-Yeol Yang
Kweon Yu
Doo-Sang Park
Hyun-Woo Oh
Erica E. Davis
Charles E. Schwartz
Jeong-Soo Lee
Hyung-Goo Kim
Cheol-Hee Kim
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2017
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-017-0168-2

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