title: Astrocyte-specific regulation of hMeCP2 expression in Drosophila.
abstract: Alterations in the expression of Methyl-CpG-binding protein 2 (MeCP2) either by mutations or gene duplication leads to a wide spectrum of neurodevelopmental disorders including Rett Syndrome and MeCP2 duplication disorder. Common features of Rett Syndrome (RTT), MeCP2 duplication disorder, and neuropsychiatric disorders indicate that even moderate changes in MeCP2 protein levels result in functional and structural cell abnormalities. In this study, we investigated two areas of MeCP2 pathophysiology using Drosophila as a model system: the effects of MeCP2 glial gain-of-function activity on circuits controlling sleep behavior, and the cell-type specific regulation of MeCP2 expression. In this study, we first examined the effects of elevated MeCP2 levels on microcircuits by expressing human MeCP2 (hMeCP2) in astrocytes and distinct subsets of amine neurons including dopamine and octopamine (OA) neurons. Depending on the cell-type, hMeCP2 expression reduced sleep levels, altered daytime/nighttime sleep patterns, and generated sleep maintenance deficits. Second, we identified a 498 base pair region of the MeCP2e2 isoform that is targeted for regulation in distinct subsets of astrocytes. Levels of the full-length hMeCP2e2 and mutant RTT R106W protein decreased in astrocytes in a temporally and spatially regulated manner. In contrast, expression of the deletion Δ166 hMeCP2 protein was not altered in the entire astrocyte population. qPCR experiments revealed a reduction in full-length hMeCP2e2 transcript levels suggesting transgenic hMeCP2 expression is regulated at the transcriptional level. Given the phenotypic complexities that are caused by alterations in MeCP2 levels, our results provide insight into distinct cellular mechanisms that control MeCP2 expression and link microcircuit abnormalities with defined behavioral deficits.
authors.affiliation: Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Hess-Homeier
authors.affiliation: Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 31040, Taiwan Brain Research Center, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Fan
authors.affiliation: Neuroscience Graduate Program, The University of Montana, Missoula, MT 59812, USA.
authors.forename: Tarun
authors.initials: T
authors.lastname: Gupta
authors.affiliation: Brain Research Center, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Ann-Shyn
authors.initials: AS
authors.lastname: Chiang
authors.affiliation: Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA Neuroscience Graduate Program, The University of Montana, Missoula, MT 59812, USA sarah.certel@umontana.edu.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Certel
keywords: Astrocytes; Drosophila; MeCP2; Rett Syndrome; Sleep