Deficiency of Meis1, a transcriptional regulator, in mice and worms: Neurochemical and behavioral characterizations with implications in the restless legs syndrome. Issue 5 (23rd September 2020)

• Record Type: Journal Article
• Authors: Lyu, Shangru; Xing, Hong; Liu, Yuning; Girdhar, Pallavi; Zhang, Keer; Yokoi, Fumiaki; Xiao, Rui; Li, Yuqing
• Is Part Of: Journal of neurochemistry. Volume 155:Issue 5(2020)
• Page Start: 522
• Page End: 537
• Publication Date: 2020-09-23
• Subjects: ferritin -- Meis1 -- restless legs syndrome -- sleep -- striatal cholinergic system -- striatal dopaminergic system; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15177
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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. Abstract : Restless leg syndrome (RLS) is a common sleep‐related sensorimotor neurological disorder. MEIS1 is associated with RLS, insomnia, and sleep regulation. Our new line of Meis1 knockout mice was hyperactive and showed increased serum ferritin. Additionally, in the striatum, knockouts had a decreased tyrosine hydroxylase (TH) protein level but increased dopamine (DA) turnover and decreased spontaneous firing regularity of cholinergic interneurons (CIN). Our data suggest that Meis1 knockout mice have RLS‐like motor restlessness, which may be related to changes in the striatal dopaminergic and cholinergic systems. Dotted arrow indicates hypothesized relationships, and solid arrows indicate there exists direct evidence.