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：

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

不宁腿综合征是一种与睡眠相关的感觉运动神经系统疾病，影响多达 10% 的人口。遗传分析已确定髓样嗜性病毒整合位点 1 ( MEIS1)，一种转录调节因子，不仅与不宁腿综合征有关，而且与失眠和睡眠的自我报告症状有关。本研究旨在确定小鼠的Meis1缺陷是否会导致不宁腿综合征样表型，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。将卵保留测定和荧光报告基因用于秀丽隐杆线虫. 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，在敲除MEIS1的直系同源物unc-62后，DRD2的直系同源物dop-3的功能减弱。此外，UNC-62敲低导致酪氨酸羟化酶的直向同源物的增强的转录，CAT- 2 MEIS1敲除小鼠是活动过度的并具有一个休息期特异性增加唤醒的可能性。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。具体而言，Meis1敲除小鼠的纹状体中 mRNA 水平增加，但酪氨酸羟化酶的蛋白质水平降低。此外，Meis1基因敲除小鼠纹状体多巴胺周转增加，纹状体胆碱能中间神经元的自发放电规律降低。我们的数据表明，Meis1基因敲除小鼠有不安腿综合征样运动不安和血清铁蛋白水平的变化。症状可能与功能失调的多巴胺能和胆碱能系统有关。