Deficiency of Meis1, a transcriptional regulator, in mice and worms: Neurochemical and behavioral characterizations with implications in the restless legs syndrome.,Journal of Neurochemistry

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Deficiency of Meis1, a transcriptional regulator, in mice and worms: Neurochemical and behavioral characterizations with implications in the restless legs syndrome.
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-09-10 , DOI: 10.1111/jnc.15177
Shangru Lyu ₁ , Hong Xing ₁ , Yuning Liu ₁ , Pallavi Girdhar ₁ , Keer Zhang ₁ , Fumiaki Yokoi ₁ , Rui Xiao ₂ , Yuqing Li ₁

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Restless legs syndrome is a sleep‐related sensorimotor neurological disease affecting up to 10% of the population. Genetic analyses have identified Myeloid Ecotropic viral Integration Site 1 (MEIS1), a transcriptional regulator, to be associated with not only the restless legs syndrome but also self‐reported symptoms of insomnia and sleep. This study is to determine if Meis1 deficiency in mice can lead to restless legs syndrome‐like phenotypes, and if it is the case, what the underlying mechanisms are. We used two genetic model systems, Caenorhabditis elegans and mice. Egg retention assay and fluorescent reporters were used with C. elegans. For mice, we performed behavioral tests, serum and brain iron detection, qRT‐PCR, western blot, immunohistochemistry, and in vitro brain‐slice recording. Our results showed that with C. elegans, the function of dop‐3, an orthologue of DRD2, was diminished after the knockdown of unc‐62, an ortholog of MEIS1. Additionally, unc‐62 knockdown led to enhanced transcription of the orthologue of tyrosine hydroxylase, cat‐2. Meis1 knockout mice were hyperactive and had a rest‐phase‐specific increased probability of waking. Moreover, Meis1 knockout mice had increased serum ferritin and altered striatal dopaminergic and cholinergic systems. Specifically, Meis1 knockout mice showed an increased mRNA level but decreased protein level of tyrosine hydroxylase in the striatum. Furthermore, Meis1 knockout mice had increased striatal dopamine turnover and decreased spontaneous firing regularity of striatal cholinergic interneurons. Our data suggest that Meis1 knockout mice have restless legs syndrome‐like motor restlessness and changes in serum ferritin levels. The symptoms may be related to dysfunctional dopaminergic and cholinergic systems.

中文翻译：

小鼠和线虫中转录调节因子 Meis1 的缺乏：神经化学和行为特征对不宁腿综合征的影响。

不宁腿综合症是一种与睡眠相关的感觉运动神经系统疾病，影响高达 10% 的人口。遗传分析发现，转录调节因子髓样亲向性病毒整合位点 1 ( MEIS1)不仅与不宁腿综合征有关，还与自我报告的失眠和睡眠症状有关。本研究旨在确定小鼠中Meis1缺陷是否会导致类似不宁腿综合征的表型，如果是这种情况，其潜在机制是什么。我们使用了两种遗传模型系统：秀丽隐杆线虫和小鼠。卵保留测定和荧光报告仪用于秀丽隐杆线虫。对于小鼠，我们进行了行为测试、血清和脑铁检测、qRT-PCR、蛋白质印迹、免疫组织化学和体外脑切片记录。我们的结果表明，对于秀丽隐杆线虫， dop-3 （ DRD2的直向同源物）的功能在敲除unc-62 （ MEIS1的直向同源物）后减弱。此外， unc-62敲低导致酪氨酸羟化酶的直系同源物cat -2 的转录增强。 Meis1敲除小鼠表现出过度活跃，并且具有特定于休息阶段的觉醒概率增加。此外， Meis1基因敲除小鼠血清铁蛋白增加，纹状体多巴胺能和胆碱能系统发生改变。具体来说， Meis1敲除小鼠纹状体中酪氨酸羟化酶的 mRNA 水平增加，但蛋白质水平降低。此外， Meis1基因敲除小鼠的纹状体多巴胺更新增加，纹状体胆碱能中间神经元的自发放电规律性降低。我们的数据表明， Meis1基因敲除小鼠具有不宁腿综合征样运动不安和血清铁蛋白水平的变化。这些症状可能与多巴胺能和胆碱能系统功能失调有关。

更新日期：2020-09-10

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