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

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.

Investigation of dopaminergic signalling in Meis homeobox 1 (Meis1) deficient mice as an animal model of restless legs syndrome

“…Finally, the number of ChAT + cholinergic interneurones, an important modulator of MSNs, was not altered in the Meis1 +/− striatum. This observation is in agreement with a recent report of normal content of these interneurones in a distinct model of Meis1 deficiency (Lyu et al., 2020). However, Lyu et al reported that Meis1 deficiency affected synchronous firing of these cells, which remains to be evaluated in the models we investigated here.…”

“…A recent study by Lyu et al reported hyperac-tivity of Meis1-deficient mice resulting from deletion of the eighth exon of the Meis1 gene. This mouse model displayed decreased tyrosine hydroxylase protein expression associated with an increased dopaminergic turnover supporting abnormal signalling of dopaminergic neurones projecting to the striatum, although without any apparent changes in striatal DRD2 protein expression (Lyu et al, 2020).…”

“…In both models, no obvious motor coordination abnormalities were detected. Additionally, Meis1 ‐deficient mice lacking the eighth exon of Meis1 also displayed motor hyperactivity, which was restricted to the light period when analysed by spontaneous activity in running wheel, and observed throughout the 24 hr of the light–dark cycle when analysed in an open field (Lyu et al., 2020).…”

“…A recent study by Lyu et al reported hyperactivity of Meis1 ‐deficient mice resulting from deletion of the eighth exon of the Meis1 gene. This mouse model displayed decreased tyrosine hydroxylase protein expression associated with an increased dopaminergic turnover supporting abnormal signalling of dopaminergic neurones projecting to the striatum, although without any apparent changes in striatal DRD2 protein expression (Lyu et al., 2020). The mammalian striatum is also populated by aspiny neurones, including cholinergic interneurones expressing choline acetyltransferase (ChAT), which are important modulators of dopaminergic control of major striatal output pathways and relevant motor and cognitive functions (Semba et al., 1988).…”

MEIS1 in Hematopoiesis and Cancer. How MEIS1-PBX Interaction Can Be Used in Therapy

“…Genome-wide association studies have linked polymorphism of MEIS1 to an increased risk of "Restless legs syndrome" [11][12][13][14]. MEIS1 has also been linked to insomnia and sleep disorders [15][16][17]; in addition, it appears to be an essential regulator of the cardiomyocytes cell cycle [18][19][20].…”