Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism.
Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism.
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DOI：
10.1186/s13229-017-0168-2
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发表时间：
2017
期刊：
影响因子：
6.2
通讯作者：
Kim CH
中科院分区：
文献类型：
--
作者：
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
DYRK 1A定位于21 q22的唐氏综合征关键区域。据报道，这种激酶编码基因的突变会导致人类智力残疾或自闭症相关的小头畸形。在小鼠模型中，通过过表达模拟唐氏综合征表型的Dyrk 1a，重现了伴有小头畸形的智力残疾。然而，考虑到纯合子敲除（KO）小鼠的胚胎致死性，没有小鼠模型研究可以提供足够的证据将Dyrk 1a功能障碍与自闭症联系起来。为了了解小头畸形和自闭症谱系障碍（ASD）的分子机制，我们使用斑马鱼建立了体内dyrk 1aa KO模型。我们使用微阵列分析鉴定了一例DYRK 1A基因突变的患者。绕过小鼠模型研究的障碍，我们使用转录激活因子样效应核酸酶（TALEN）介导的基因组编辑产生了dyrk 1aa KO斑马鱼。对于社会行为测试，我们已经建立了社会互动测试，浅滩试验和群体行为试验。在分子生物学分析方面，我们利用包括c-fos和crh在内的多种应激反应分子标记探针，通过原位杂交检测了dyrk 1aa基因敲除斑马鱼特定脑区的神经元活动。微阵列检测到一个基因内微缺失DYRK 1A在个体与小头畸形和自闭症。从社会互动和群体行为的行为测试中，dyrk 1aa KO斑马鱼表现出社会障碍，在脊椎动物模型中再现了人类自闭症表型。通过对c-fos和crh表达的分子分析进一步证实了dyrk 1aa基因敲除斑马鱼的社会性障碍。c-fos和crh在特定下丘脑区域的转录表达低于野生型鱼，表明KO鱼的大脑较少被社会环境激活。在这项研究中，我们建立了一个斑马鱼模型，以验证脊椎动物自闭症的候选基因。这些结果说明DYRK 1A的功能缺陷是自闭症的潜在疾病机制。我们还提出了简单的社会行为测定作为更广泛的研究自闭症候选基因的工具。本文的在线版本（10.1186/s13229-017-0168-2）包含补充材料，可供授权用户使用。
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. The online version of this article (10.1186/s13229-017-0168-2) contains supplementary material, which is available to authorized users.
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