MECP2 impairs neuronal structure by regulating KIBRA

Williams, Alison A.; White, Robin; Siniard, Ashley L.; Corneveaux, Jason J.; Huentelman, Matt; Duch, Carsten

doi:10.1016/j.nbd.2016.03.019

Cited by 4 publications

(6 citation statements)

References 58 publications

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“…MN5 is well suited for analyzing genetic interactions and cellular consequences of MECP2 gain-of-function alleles because it is (i) individually identifiable, (ii) displays a stereotyped and well quantified morphology [ 48 ], (iii) is physiologically well described [ 49 – 52 ], and (iv) can be addressed by targeted genetic manipulation [ 18 , 19 , 53 , 54 ] with the binary GAL4-UAS expression system [ 55 ]. We use the C380-Gal4; Cha-Gal80 driver line to heterologously express human MECP2 in MN5 labeled with GFP [ 18 , 19 , 48 , 49 , 53 , 54 ]. C380-GAL4 expresses in about 30 neurons per hemisegment of the Drosophila ventral nerve cord (VNC), most of which are glutamatergic motoneurons including MN5 ( Fig 1b ) [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

“…On the cellular level, MeCP2 mis-regulation negatively impacts dendritic structure as shown in patients [ 12 ], in vivo in mouse [ 13 – 16 ], Xenopus [ 17 ], and Drosophila [ 18 , 19 ] models, as well as in primary neuron and slice cultures [ 20 , 21 ]. Additionally, overexpression of MECP2 , specifically the E2 isoform, contributes to apoptosis in cultured neurons [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…When expressed in Drosophila , human MeCP2 will associate with chromatin, modify transcription, and become phosphorylated at the same sites as in mammals [ 28 ]. Furthermore, expressing human MECP2 in the fly has helped identify novel MeCP2 interactors that have been subsequently validated in mouse model systems [ 19 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations

Williams

Mehler

Mueller³

et al. 2016

PLoS ONE

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Methyl-CpG binding protein 2 (MeCP2) is a widely abundant, multifunctional protein most highly expressed in post-mitotic neurons. Mutations causing Rett syndrome and related neurodevelopmental disorders have been identified along the entire MECP2 locus, but symptoms vary depending on mutation type and location. C-terminal mutations are prevalent, but little is known about the function of the MeCP2 C-terminus. We employ the genetic efficiency of Drosophila to provide evidence that expression of p.Arg294* (more commonly identified as R294X), a human MECP2 E2 mutant allele causing truncation of the C-terminal domains, promotes apoptosis of identified neurons in vivo. We confirm this novel finding in HEK293T cells and then use Drosophila to map the region critical for neuronal apoptosis to a small sequence at the end of the C-terminal domain. In vitro studies in mammalian systems previously indicated a role of the MeCP2 E2 isoform in apoptosis, which is facilitated by phosphorylation at serine 80 (S80) and decreased by interactions with the forkhead protein FoxG1. We confirm the roles of S80 phosphorylation and forkhead domain transcription factors in affecting MeCP2-induced apoptosis in Drosophila in vivo, thus indicating mechanistic conservation between flies and mammalian cells. Our findings are consistent with a model in which C- and N-terminal interactions are required for healthy function of MeCP2.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations

Williams

Mehler

Mueller³

et al. 2016

PLoS ONE

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“…Wwc1 is known to be involved in memory formation, synaptic plasticity, and neuronal morphology. It has also been reported that too much or too little expression of Wwc1 affects neuronal morphology or synapse formation [ 54 , 55 , 56 ]. We hypothesized that de novo methylation of the Wwc1 hyperDMR is important for activity-induced synaptogenesis.…”

Section: Resultsmentioning

confidence: 99%

Neuronal activation modulates enhancer activity of genes for excitatory synaptogenesis through <i>de novo</i> DNA methylation

Kameda

Nakashima

Takizawa

et al. 2021

Journal of Reproduction and Development

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Post-mitotic neurons do exhibit DNA methylation changes, contrary to the longstanding belief that the epigenetic pattern in terminally differentiated cells is essentially unchanged. While the mechanism and physiological significance of DNA demethylation in neurons have been extensively elucidated, the occurrence of de novo DNA methylation and its impacts have been much less investigated. In the present study, we showed that neuronal activation induces de novo DNA methylation at enhancer regions, which can repress target genes in primary cultured hippocampal neurons. The functional significance of this de novo DNA methylation was underpinned by the demonstration that inhibition of DNA methyltransferase (DNMT) activity decreased neuronal activity-induced excitatory synaptogenesis. Overexpression of WW and C2 domain-containing 1 (Wwc1), a representative target gene of de novo DNA methylation, could phenocopy this DNMT inhibition-induced decrease in synaptogenesis. We found that both DNMT1 and DNMT3a were required for neuronal activity-induced de novo DNA methylation of the Wwc1 enhancer. Taken together, we concluded that neuronal activity-induced de novo DNA methylation that affects gene expression has an impact on neuronal physiology that is comparable to that of DNA demethylation. Since the different requirements of DNMTs for germ cell and embryonic development are known, our findings also have considerable implications for future studies on epigenomics in the field of reproductive biology.

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“…MeCP2 gain of function is associated with MeCP2 duplication syndrome (MDS), which causes severe mental retardation, stunted motor development, early-onset hypotonia, epileptic seizures, and progressive spasticity [ 81 ], and interestingly is also associated with mood alterations such as anxiety, depression, and an autistic-like phenotype [ 82 ]. In contrast to MeCP2 loss-of-function models, MeCP2 gain-of-function models show rescue of dendritic defects [ 83 ] and display augmented paired-pulse facilitation [ 84 , 85 ] indicative of a tight relationship between MeCP2 and synaptic plasticity. Most recent studies have shown that an aberrant increase in the formation and stabilization of dendritic spines occurs in the cerebral cortex of the mouse model of MECP2-duplication syndrome and seems to be mediated by hyperactivation of the ERK pathway [ 86 , 87 ], a major regulator of clustered spine stabilization [ 88 ].…”

Section: Mecp2 and Synaptic Plasticitymentioning

confidence: 99%

The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression

Sánchez-Lafuente

Kalynchuk

Caruncho

et al. 2022

Cells

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Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that is highly abundant in the brain. It binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. MeCP2 has mainly been studied for its role in neurodevelopmental disorders, but alterations in MeCP2 are also present in stress-related disorders such as major depression. Impairments in both stress regulation and synaptic plasticity are associated with depression, but the specific mechanisms underlying these changes have not been identified. Here, we review the interplay between stress, synaptic plasticity, and MeCP2. We focus our attention on the transcriptional regulation of important neuronal plasticity genes such as BDNF and reelin (RELN). Moreover, we provide evidence from recent studies showing a link between chronic stress-induced depressive symptoms and dysregulation of MeCP2 expression, underscoring the role of this protein in stress-related pathology. We conclude that MeCP2 is a promising target for the development of novel, more efficacious therapeutics for the treatment of stress-related disorders such as depression.

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MECP2 impairs neuronal structure by regulating KIBRA

Cited by 4 publications

References 58 publications

Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations

Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations

Neuronal activation modulates enhancer activity of genes for excitatory synaptogenesis through <i>de novo</i> DNA methylation

The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression

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