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See detailOligodendrocyte lineage cells contribute unique features to rett syndrome neuropathology
Nguyen, Minh Vu Chong UL; Felice, Christy A.; Du, Fang et al

in Journal of Neuroscience (2013), 33(48), 18764-18774

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 ... [more ▼]

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. © 2013 the authors. [less ▲]

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See detailMeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain
Nguyen, Minh Vu Chong UL; Du, Fang; Felice, Christy A. et al

in Journal of Neuroscience (2012), 32(29), 10021-10034

Mutations in the X-linked gene, methyl-CpG binding protein 2 (Mecp2), underlie a wide range of neuropsychiatric disorders, most commonly, Rett Syndrome (RTT), a severe autism spectrum disorder that ... [more ▼]

Mutations in the X-linked gene, methyl-CpG binding protein 2 (Mecp2), underlie a wide range of neuropsychiatric disorders, most commonly, Rett Syndrome (RTT), a severe autism spectrum disorder that affects approximately one in 10,000 female live births. Because mutations in the Mecp2 gene occur in the germ cells with onset of neurological symptoms occurring in early childhood, the role of MeCP2 has been ascribed to brain maturation at a specific developmental window. Here, we show similar kinetics of onset and progression of RTT-like symptoms in mice, including lethality, if MeCP2 is removed postnatally during the developmental stage that coincides with RTT onset, or adult stage. For the first time, we show that brains that lose MeCP2 at these two different stages are actively shrinking, resulting in higher than normal neuronal cell density. Furthermore, we show that mature dendritic arbors of pyramidal neurons are severely retracted and dendritic spine density is dramatically reduced. In addition, hippocampal astrocytes have significantly less complex ramified processes. These changes accompany a striking reduction in the levels of several synaptic proteins, including CaMKII α/β, AMPA, and NMDA receptors, and the synaptic vesicle proteins Vglut and Synapsin, which represent critical modifiers of synaptic function and dendritic arbor structure. Importantly, the mRNA levels of these synaptic proteins remains unchanged, suggesting that MeCP2 likely regulates these synaptic proteins post-transcriptionally, directly or indirectly. Our data suggest a crucial role for MeCP2 in post-transcriptional regulation of critical synaptic proteins involved in maintaining mature neuronal networks during late stages of postnatal brain development. © 2012 the authors. [less ▲]

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