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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Article number168
JournalMolecular Autism
Volume8
Issue number1
DOIs
StatePublished - Sep 29 2017

Fingerprint

Zebrafish
Autistic Disorder
Down Syndrome
Microcephaly
Genes
Interpersonal Relations
Intellectual Disability
Vertebrates
Fishes
Phenotype
Mutation
Brain
Microarray Analysis
Knockout Mice
In Situ Hybridization
Phosphotransferases
Animal Models

Keywords

  • Autism
  • DYRK1A
  • Down syndrome
  • Group behavior
  • Knockout
  • Shoaling
  • Social interaction
  • Zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Neuroscience
  • Developmental Biology
  • Psychiatry and Mental health

Cite this

Kim, O. H., Cho, H. J., Han, E., Hong, T. I., Ariyasiri, K., Choi, J. H., ... Kim, C. H. (2017). Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism. Molecular Autism, 8(1), [168]. https://doi.org/10.1186/s13229-017-0168-2

Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism. / Kim, Oc Hee; Cho, Hyun Ju; Han, Enna; Hong, Ted Inpyo; Ariyasiri, Krishan; Choi, Jung Hwa; Hwang, Kyu Seok; Jeong, Yun Mi; Yang, Se Yeol; Yu, Kweon; Park, Doo Sang; Oh, Hyun Woo; Davis, Erica E.; Schwartz, Charles E.; Lee, Jeong Soo; Kim, Hyung Goo; Kim, Cheol Hee.

In: Molecular Autism, Vol. 8, No. 1, 168, 29.09.2017.

Research output: Contribution to journalArticle

Kim, OH, Cho, HJ, Han, E, Hong, TI, Ariyasiri, K, Choi, JH, Hwang, KS, Jeong, YM, Yang, SY, Yu, K, Park, DS, Oh, HW, Davis, EE, Schwartz, CE, Lee, JS, Kim, HG & Kim, CH 2017, 'Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism', Molecular Autism, vol. 8, no. 1, 168. https://doi.org/10.1186/s13229-017-0168-2
Kim, Oc Hee ; Cho, Hyun Ju ; Han, Enna ; Hong, Ted Inpyo ; Ariyasiri, Krishan ; Choi, Jung Hwa ; Hwang, Kyu Seok ; Jeong, Yun Mi ; Yang, Se Yeol ; Yu, Kweon ; Park, Doo Sang ; Oh, Hyun Woo ; Davis, Erica E. ; Schwartz, Charles E. ; Lee, Jeong Soo ; Kim, Hyung Goo ; Kim, Cheol Hee. / Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism. In: Molecular Autism. 2017 ; Vol. 8, No. 1.
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AU - Kim, Oc Hee

AU - Cho, Hyun Ju

AU - Han, Enna

AU - Hong, Ted Inpyo

AU - Ariyasiri, Krishan

AU - Choi, Jung Hwa

AU - Hwang, Kyu Seok

AU - Jeong, Yun Mi

AU - Yang, Se Yeol

AU - Yu, Kweon

AU - Park, Doo Sang

AU - Oh, Hyun Woo

AU - Davis, Erica E.

AU - Schwartz, Charles E.

AU - Lee, Jeong Soo

AU - Kim, Hyung Goo

AU - Kim, Cheol Hee

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N2 - 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.

AB - 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.

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