title: Oligodendrocyte lineage cells contribute unique features to Rett syndrome neuropathology.
abstract: Mutations in the methyl-CpG binding protein 2 gene, Mecp2, affect primarily the brain and lead to a wide range of neuropsychiatric disorders, most commonly Rett syndrome (RTT). Although the neuropathology of RTT is well understood, the cellular and molecular mechanism(s), which lead to the disease initiation and progression, has yet to be elucidated. RTT was initially attributed only to neuronal dysfunction, but our recent studies and those of others show that RTT is not exclusively neuronal but rather also involves interactions between neurons and glia. Importantly, studies have shown that MeCP2-restored astrocytes and microglia are able to attenuate the disease progression in otherwise MeCP2-null mice. Here we show that another type of glia, oligodendrocytes, and their progenitors are also involved in manifestation of specific RTT symptoms. Mice that lost MeCP2 specifically in the oligodendrocyte lineage cells, although overall normal, were more active and developed severe hindlimb clasping phenotypes. Inversely, restoration of MeCP2 in oligodendrocyte lineage cells, in otherwise MeCP2-null mice, although only mildly prolonging their lifespan, significantly improved the locomotor deficits and hindlimb clasping phenotype, both in male and female mice, and fully restored the body weight in male mice. Finally, we found that the level of some myelin-related proteins was impaired in the MeCP2-null mice. Expression of MeCP2 in oligodendrocytes of these mice only partially restored their expression, suggesting that there is a non-cell-autonomous effect by other cell types in the brains on the expression of myelin-related proteins in oligodendrocytes.
authors.affiliation: Department of Biochemistry and Cell Biology and Department of Psychology, Stony Brook University, Stony Brook, New York 11794, and Vollum Institute and Howard Hughes Medical Institute, Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Minh Vu Chuong
authors.initials: MV
authors.lastname: Nguyen
authors.forename: Christy A
authors.initials: CA
authors.lastname: Felice
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Covey
authors.forename: John K
authors.initials: JK
authors.lastname: Robinson
authors.forename: Gail
authors.initials: G
authors.lastname: Mandel
authors.forename: Nurit
authors.initials: N
authors.lastname: Ballas
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology; D015153:Blotting, Western; D019070:Cell Lineage / Q000502:physiology*; D003624:Darkness; D005260:Female; D018737:Hand Strength / Q000502:physiology; D006614:Hindlimb / Q000502:physiology; D007150:Immunohistochemistry; D008027:Light; D008124:Locomotion / Q000502:physiology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000502:physiology; D051379:Mice; D009154:Mutation / Q000235:genetics / Q000502:physiology; D004676:Myelin Basic Protein / Q000502:physiology; D009836:Oligodendroglia / Q000473:pathology*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015518:Rett Syndrome / Q000473:pathology*
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D004676:Myelin Basic Protein