Dataset Information

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

ABSTRACT: 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.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.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.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.

SUBMITTER: Kim OH

PROVIDER: S-EPMC5622473 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Zebrafish knockout of Down syndrome gene, <i>DYRK1A</i>, shows social impairments relevant to autism.

Kim Oc-Hee OH Cho Hyun-Ju HJ Han Enna E Hong Ted Inpyo TI Ariyasiri Krishan K Choi Jung-Hwa JH Hwang Kyu-Seok KS Jeong Yun-Mi YM Yang Se-Yeol SY Yu Kweon K Park Doo-Sang DS Oh Hyun-Woo HW Davis Erica E EE Schwartz Charles E CE Lee Jeong-Soo JS Kim Hyung-Goo HG Kim Cheol-Hee CH

Molecular autism 20170929

<h4>Background</h4><i>DYRK1A</i> 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 <i>Dyrk1a</i> which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present ...[more]

PMID: 29021890

Similar Datasets

Project description:Overexpression of Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS-associated phenotypes have been largely unsuccessful. Epigallocatechin-3-gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS-associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue-specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue-specific-sensitive periods when Dyrk1a regulates cellular processes that shape the long-term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

Dataset Information

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

Publications

Zebrafish knockout of Down syndrome gene, <i>DYRK1A</i>, shows social impairments relevant to autism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets