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Adrian Bird - One of the best experts on this subject based on the ideXlab platform.
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mathematical modelling reveals how MECP2 restrains transcriptional elongation in human neurons
bioRxiv, 2018Co-Authors: Justyna Cholewawaclaw, Ruth Shah, Shaun Webb, Kashyap Chhatbar, Oliver Pusch, Philip Greulich, Bartlomiej Waclaw, Adrian BirdAbstract:Gene expression patterns depend on the interaction of diverse transcription factors with their target genes. While many factors have a restricted number of targets, some appear to affect transcription globally. An example of the latter is MECP2; an abundant chromatin-associated protein that is mutated in the neurological disorder Rett Syndrome. To understand how MECP2 affects transcription, we integrated mathematical modelling with quantitative experimental analysis of human neurons expressing graded levels of MECP2. We first used a model of MECP2-DNA binding to demonstrate that changes in gene expression reflect MECP2 density downstream of transcription initiation. We then tested five biologically plausible hypotheses for the effect of MECP2 on transcription. The only model compatible with the data involved slowing down of RNA polymerase II by MECP2, causing reduced transcript output due to polymerase queueing. Our general approach may prove fruitful in deciphering the mechanisms by which other global regulators choreograph gene expression.
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activity dependent phosphorylation of MECP2 threonine 308 regulates interaction with ncor
Nature, 2013Co-Authors: Daniel H Ebert, Sonia Cohen, Harrison W Gabel, Nathaniel R. Kastan, Nathaniel D Robinson, Linda Hu, Adrija J Navarro, Matthew J Lyst, Robert Ekiert, Adrian BirdAbstract:Rett syndrome is caused by mutations in MECP2, and this study identifies a site on MECP2, T308, whose phosphorylation is regulated by neuronal activity: phosphorylation of T308 blocks the interaction of MECP2 with the NCoR co-repressor complex, suppressing MECP2's ability to repress transcription, and mice carrying mutations of MECP2 T308 show Rett-syndrome-related symptoms.
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the methyl cpg binding protein MECP2 links dna methylation to histone methylation
Journal of Biological Chemistry, 2003Co-Authors: Francois Fuks, Adrian Bird, Paul J Hurd, Daniel Wolf, Tony KouzaridesAbstract:Abstract DNA methylation plays an important role in mammalian development and correlates with chromatin-associated gene silencing. The recruitment of MECP2 to methylated CpG dinucleotides represents a major mechanism by which DNA methylation can repress transcription. MECP2 silences gene expression partly by recruiting histone deacetylase (HDAC) activity, resulting in chromatin remodeling. Here, we show that MECP2 associates with histone methyltransferase activity in vivo and that this activity is directed against Lys9 of histone H3. Two characterized repression domains of MECP2 are involved in tethering the histone methyltransferase to MECP2. We asked if MECP2 can deliver Lys9 H3 methylation to the H19 gene, whose activity it represses. We show that the presence of MECP2 on nucleosomes within the repressor region of the H19 gene (the differentially methylated domain) coincides with an increase in H3 Lys9methylation. Our data provide evidence that MECP2 reinforces a repressive chromatin state by acting as a bridge between two global epigenetic modifications, DNA methylation and histone methylation.
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a mouse MECP2 null mutation causes neurological symptoms that mimic rett syndrome
Nature Genetics, 2001Co-Authors: Jacky Guy, Brian Hendrich, Megan C Holmes, Joanne E Martin, Adrian BirdAbstract:Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000-15,000 births. Affected females develop normally for 6-18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with MECP2-null embryonic stem cells indicated that MECP2 is essential for mouse embryogenesis. Here we generate mice lacking MECP2 using Cre-loxP technology. Both MECP2-null mice and mice in which MECP2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MECP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MECP2.
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mbd2 is a transcriptional repressor belonging to the mecp1 histone deacetylase complex
Nature Genetics, 1999Co-Authors: Huckhui Ng, Brian Hendrich, Colin A Johnson, Bryan M Turner, Hediye Erdjumentbromage, Paul Tempst, Yi Zhang, Adrian BirdAbstract:Mammalian DNA is methylated at many CpG dinucleotides. The biological consequences of methylation are mediated by a family of methyl-CpG binding proteins1,2,3,4. The best characterized family member is MECP2, a transcriptional repressor that recruits histone deacetylases5,6,7. Our report concerns MBD2, which can bind methylated DNA in vivo and in vitro 4 and has been reported to actively demethylate DNA (ref. 8). As DNA methylation causes gene silencing, the MBD2 demethylase is a candidate transcriptional activator. Using specific antibodies, however, we find here that MBD2 in HeLa cells is associated with histone deacetylase (HDAC) in the MeCP1 repressor complex1,9. An affinity-purified HDAC1 corepressor complex10,11 also contains MBD2, suggesting that MeCP1 corresponds to a fraction of this complex. Exogenous MBD2 represses transcription in a transient assay, and repression can be relieved by the deacetylase inhibitor trichostatin A (TSA; ref. 12). In our hands, MBD2 does not demethylate DNA. Our data suggest that HeLa cells, which lack the known methylation-dependent repressor MECP2, use an alternative pathway involving MBD2 to silence methylated genes.
Huda Y. Zoghbi - One of the best experts on this subject based on the ideXlab platform.
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MECP2 binds to non cg methylated dna as neurons mature influencing transcription and the timing of onset for rett syndrome
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Lin Chen, Huda Y. Zoghbi, Steven Andrew Baker, Chad A Shaw, Kaifu Chen, Laura A LaveryAbstract:Decades of research have not deciphered the mechanism by which methyl-CpG binding protein 2 (MECP2) regulates transcription and why Rett symptoms manifest 1 to 2 y after birth. We hypothesized that the temporal dynamics of MECP2 binding might provide an answer. We developed mice with an EGFP-tagged MECP2 allele to identify high-resolution MECP2 binding profiles in the adult mouse brain. Using genomic binding profiles, methylation maps, and mRNA deep-sequencing data, we found MECP2 binds to non-CG methylation (mCH, not mCG) to regulate expression of genes altered in mouse models of MECP2 disorders. These data and the parallel timing of mCH and MECP2 postnatal accumulation suggest MECP2 binds mCH as neurons mature to regulate gene expression, offering an explanation for the delayed onset of Rett.
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rett causing mutations reveal two domains critical for MECP2 function and for toxicity in MECP2 duplication syndrome mice
eLife, 2014Co-Authors: Huda Y. Zoghbi, Laura Dean Heckman, Maria H ChahrourAbstract:Loss of function of the X-linked gene encoding methyl-CpG binding protein 2 (MECP2) causes the progressive neurological disorder Rett syndrome (RTT). Conversely, duplication or triplication of Xq28 causes an equally wide-ranging progressive neurological disorder, MECP2 duplication syndrome, whose features overlap somewhat with RTT. To understand which MECP2 functions cause toxicity in the duplication syndrome, we generated mouse models expressing endogenous MECP2 along with a RTT-causing mutation in either the methyl-CpG binding domain (MBD) or the transcriptional repression domain (TRD). We determined that both the MBD and TRD must function for doubling MECP2 to be toxic. Mutating the MBD reproduces the null phenotype and expressing the TRD mutant produces milder RTT phenotypes, yet both mutations are harmless when expressed with endogenous MECP2. Surprisingly, mutating the TRD is more detrimental than deleting the entire C-terminus, indicating a dominant-negative effect on MECP2 function, likely due to the disruption of a basic cluster.
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crh and oprm1 mediate anxiety related behavior and social approach in a mouse model of MECP2 duplication syndrome
Nature Genetics, 2012Co-Authors: Rodney C Samaco, Bryan E Mcgill, Chad A Shaw, Caleigh Mandelbrehm, Christopher M Mcgraw, Huda Y. ZoghbiAbstract:Genomic duplications spanning Xq28 are associated with a spectrum of phenotypes, including anxiety and autism. The minimal region shared among affected individuals includes MECP2 and IRAK1, although it is unclear which gene when overexpressed causes anxiety and social behavior deficits. We report that doubling MECP2 levels causes heightened anxiety and autism-like features in mice and alters the expression of genes that influence anxiety and social behavior, such as Crh and Oprm1. To test the hypothesis that alterations in these two genes contribute to heightened anxiety and social behavior deficits, we analyzed MECP2 duplication mice (MECP2-TG1) that have reduced Crh and Oprm1 expression. In MECP2-TG1 animals, reducing the levels of Crh or its receptor, Crhr1, suppressed anxiety-like behavior; in contrast, reducing Oprm1 expression improved abnormal social behavior. These data indicate that increased MECP2 levels affect molecular pathways underlying anxiety and social behavior and provide new insight into potential therapies for MECP2-related disorders.
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mouse models of MECP2 disorders share gene expression changes in the cerebellum and hypothalamus
Human Molecular Genetics, 2009Co-Authors: Shay Benshachar, Maria H Chahrour, Christina Thaller, Chad A Shaw, Huda Y. ZoghbiAbstract:A group of post-natal neurodevelopmental disorders collectively referred to as MECP2 disorders are caused by aberrations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Loss of MECP2 function causes Rett syndrome (RTT), whereas increased copy number of the gene causes MECP2 duplication or triplication syndromes. MECP2 acts as a transcriptional repressor, however the gene expression changes observed in the hypothalamus of MECP2 disorder mouse models suggest that MECP2 can also upregulate gene expression, given that the majority of genes are downregulated upon loss of MECP2 and upregulated in its presence. To determine if this dual role of MECP2 extends beyond the hypothalamus, we studied gene expression patterns in the cerebellum of MECP2-null and MECP2-Tg mice, modeling RTT and MECP2 duplication syndrome, respectively. We found that abnormal MECP2 dosage causes alterations in the expression of hundreds of genes in the cerebellum. The majority of genes were upregulated in MECP2-Tg mice and downregulated in MECP2-null mice, consistent with a role for MECP2 as a modulator that can both increase and decrease gene expression. Interestingly, many of the genes altered in the cerebellum, particularly those increased by the presence of MECP2 and decreased in its absence, were similarly altered in the hypothalamus. Our data suggest that either gain or loss of MECP2 results in gene expression changes in multiple brain regions and that some of these changes are global. Further delineation of the expression pattern of MECP2 target genes throughout the brain might identify subsets of genes that are more amenable to manipulation, and can thus be used to modulate some of the disease phenotypes.
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MECP2 Controls Excitatory Synaptic Strength by Regulating Glutamatergic Synapse Number
Neuron, 2007Co-Authors: Hsiao-tuan Chao, Huda Y. Zoghbi, Christian RosenmundAbstract:Summary MECP2 is a transcriptional repressor critical for normal neurological function. Prior studies demonstrated that either loss or doubling of MECP2 results in postnatal neurodevelopmental disorders. To understand the impact of MECP2 expression on neuronal function, we studied the synaptic properties of individual neurons from mice that either lack or express twice the normal levels of MECP2. Hippocampal glutamatergic neurons that lack MECP2 display a 46% reduction in synaptic response, whereas neurons with doubling of MECP2 exhibit a 2-fold enhancement in synaptic response. Further analysis shows that these changes were primarily due to the number of synapses formed. These results reveal that MECP2 is a key rate-limiting factor in regulating glutamatergic synapse formation in early postnatal development and that changes in excitatory synaptic strength may underlie global network alterations in neurological disorders due to altered MECP2 levels.
Yehezkel Sztainberg - One of the best experts on this subject based on the ideXlab platform.
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antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome
Science Translational Medicine, 2021Co-Authors: Yingyao Shao, Yehezkel Sztainberg, Qi Wang, Sameer S Bajikar, Alexander J TrostleAbstract:Many intellectual disability disorders are due to copy number variations, and, to date, there have been no treatment options tested for this class of diseases. MECP2 duplication syndrome (MDS) is one of the most common genomic rearrangements in males and results from duplications spanning the methyl-CpG binding protein 2 (MECP2) gene locus. We previously showed that antisense oligonucleotide (ASO) therapy can reduce MECP2 protein amount in an MDS mouse model and reverse its disease features. This MDS mouse model, however, carried one transgenic human allele and one mouse allele, with the latter being protected from human-specific MECP2-ASO targeting. Because MECP2 is a dosage-sensitive protein, the ASO must be titrated such that the amount of MECP2 is not reduced too far, which would cause Rett syndrome. Therefore, we generated an "MECP2 humanized" MDS model that carries two human MECP2 alleles and no mouse endogenous allele. Intracerebroventricular injection of the MECP2-ASO efficiently down-regulated MECP2 expression throughout the brain in these mice. Moreover, MECP2-ASO mitigated several behavioral deficits and restored expression of selected MECP2-regulated genes in a dose-dependent manner without any toxicity. Central nervous system administration of MECP2-ASO is therefore well tolerated and beneficial in this mouse model and provides a translatable approach that could be feasible for treating MDS.
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an rna interference screen identifies druggable regulators of MECP2 stability
Science Translational Medicine, 2017Co-Authors: Steven Andrew Baker, Yehezkel Sztainberg, Laura Marie Lombardi, Manar Zaghlula, Tiemo J Klisch, Amy A TangAbstract:Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, intellectual disability (ID), and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG–binding protein 2 (MECP2) that even a twofold change in MECP2 protein—either increased or decreased—results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in MECP2 , whereas duplications spanning the MECP2 locus result in MECP2 duplication syndrome (MDS), which accounts for ~1% of X-linked ID. Despite evidence from mouse models that restoring MECP2 can reverse the course of disease, there are currently no U.S. Food and Drug Administration–approved therapies available to clinically modulate MECP2 abundance. We used a forward genetic screen against all known human kinases and phosphatases to identify druggable regulators of MECP2 stability. Two putative modulators of MECP2, HIPK2 (homeodomain-interacting protein kinase 2) and PP2A (protein phosphatase 2A), were validated as stabilizers of MECP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MECP2 in the nervous system and rescued both overexpression and motor abnormalities in a mouse model of MDS. Our findings reveal potential therapeutic targets for treating disorders of altered MECP2 dosage.
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reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides
Nature, 2015Co-Authors: Yehezkel Sztainberg, Hongmei Chen, John W Swann, Shuang Hao, Bin TangAbstract:Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MECP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MECP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MECP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MECP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional MECP2-overexpressing mouse model, here we show that correction of MECP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MECP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult symptomatic transgenic MECP2 duplication mice (MECP2-TG), and corrected MECP2 levels in lymphoblastoid cells from MECP2 duplication patients in a dose-dependent manner.
Qiang Chang - One of the best experts on this subject based on the ideXlab platform.
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regulation of neural differentiation synaptic scaling and animal behavior by MECP2 phophorylation
Neurobiology of Learning and Memory, 2019Co-Authors: Hongda Li, Xiaofen Zhong, Qiang ChangAbstract:Abstract Highly expressed in the mammalian brain and widely distributed across the genome, MECP2 is a key player in recognizing modified DNA and interpreting the epigenetic information encoded in different DNA methylation/hydroxymethylation patterns. Alterations in sequence or copy number of the X-linked human MECP2 gene cause either Rett syndrome (RTT) or MECP2 duplication syndrome. Alterations in MECP2 levels have also been identified in patients with autism. To fully understand the significant role of MECP2 in regulating the development and function of the nervous system, it is important to study all aspects of MECP2 function. Stimulus-induced MECP2 phosphorylation has been shown to influence the proliferation and differentiation of neural progenitor cells, synaptic scaling, excitatory synaptogenesis, and animal behavior. However, all of the previous functional evidence is from studying phospho-dead mutations. In addition, the relationship between phosphorylation events at multiple sites on the MECP2 protein is not well understood. Here, we report the generation of a phospho-mimic knockin MECP2 mouse line. At the synaptic and behavioral levels, the phospho-mimic MECP2 mice show phenotypes opposite to those observed in phospho-dead mutation at the same phosphorylation site. Moreover, we report opposite phenotypes between phospho-mutants of two sites on the MECP2 protein. Our new data further confirm the functional significance of specific MECP2 phosphorylation event and support the opposing regulatory role between different MECP2 phosphorylation events.
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MECP2 phosphorylation is required for modulating synaptic scaling through mglur5
The Journal of Neuroscience, 2012Co-Authors: Xiaofen Zhong, Hongda Li, Qiang ChangAbstract:MECP2 (methyl CpG binding protein 2) is a key player in recognizing methylated DNA and interpreting the epigenetic information encoded in different DNA methylation patterns. The functional significance of MECP2 to the mammalian nervous system is highlighted by the discovery that mutations in the MECP2 gene cause Rett syndrome (RTT), a devastating neurological disease that shares many features with autism. Synaptic scaling is a form of non-Hebbian homeostatic plasticity that allows neurons to regulate overall excitability in response to changes in network neuronal activity levels. While it is known that neuronal activity can induce phosphorylation of MECP2 and that MECP2 can regulate synaptic scaling, the molecular link between MECP2 phosphorylation and synaptic scaling remains undefined. We show here that MECP2 phosphorylation is specifically required for bicuculline-induced synaptic scaling down in mouse hippocampal neurons and this phenotype is mediated by mGluR5 (metabotropic glutamate receptor 5). Our results reveal an important function of MECP2 in regulating neuronal homeostasis and may eventually help us understand how MECP2 mutations cause RTT.
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the disease progression of MECP2 mutant mice is affected by the level of bdnf expression
Neuron, 2006Co-Authors: Qiang Chang, Sacha B Nelson, Gargi Khare, Vardhan S Dani, Rudolf JaenischAbstract:Mutations in the MECP2 gene cause Rett syndrome (RTT). Bdnf is a MECP2 target gene; however, its role in RTT pathogenesis is unknown. We examined Bdnf conditional mutant mice for RTT-relevant pathologies and observed that loss of BDNF caused smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. BDNF protein level was reduced in MECP2 mutant mice, and deletion of Bdnf in MECP2 mutants caused an earlier onset of RTT-like symptoms. To assess whether this interaction was functional and potentially therapeutically relevant, we increased BDNF expression in the MECP2 mutant brain with a conditional Bdnf transgene. BDNF overexpression extended the lifespan, rescued a locomotor defect, and reversed an electrophysiological deficit observed in MECP2 mutants. Our results provide in vivo evidence for a functional interaction between MECP2 and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression.
Valerie Matagne - One of the best experts on this subject based on the ideXlab platform.
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correcting deregulated fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MECP2 deficient male mice
Brain Research, 2018Co-Authors: Valerie Matagne, Matthew Frerking, Sarojini S Budden, Joyce Wondolowski, Nicholas A Delamere, Mohammad Shahidullah, Ursula S. Sandau, Sergio R. OjedaAbstract:Abstract Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MECP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of MECP2 deficient (KO) mice. To determine if Fxyd1 can rescue these RTT deficits, we studied the male progeny of Fxyd1 null males bred to heterozygous MECP2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MECP2, but it increased in mice lacking one Fxyd1 allele, suggesting that NKA activity is under Fxyd1 inhibitory control. Deletion of one Fxyd1 allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from MECP2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of MECP2 KO mice. These effects were gene-dose dependent, because the absence of Fxyd1 failed to rescue the MECP2-dependent deficits, and mimicked the effect of MECP2 deficiency in wild-type animals. These results indicate that excess of Fxyd1 in the absence of MECP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth.
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Correcting deregulated Fxydl expression rescues deficits in neuronal arborization and potassium homeostasis in MECP2 deficient male mice
Brain Research, 2018Co-Authors: Valerie Matagne, Matthew Frerking, Sarojini S Budden, Joyce Wondolowski, Nicholas A Delamere, Mohammad Shahidullah, Ursula S. Sandau, Sergio R. OjedaAbstract:Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MECP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxydl may reduce NKA activity and contribute to the neuronal phenotype of MECP2 deficient (KO) mice. To determine if Fxydl can rescue these RTT deficits, we studied the male progeny of Fxydl null males bred to heterozygous MECP2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MECP2, but it increased in mice lacking one Fxydl allele, suggesting that NKA activity is under Fxydl inhibitory control. Deletion of one Fxydl allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from MECP2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of MECP2 KO mice. These effects were gene-dose dependent, because the absence of Fxydl failed to rescue the MECP2-dependent deficits, and mimicked the effect of MECP2 deficiency in wild-type animals. These results indicate that excess of Fxydl in the absence of MECP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth. (C) 2018 Elsevier B.V. All rights reserved.
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fxyd1 is an MECP2 target gene overexpressed in the brains of rett syndrome patients and MECP2 null mice
Human Molecular Genetics, 2007Co-Authors: Vivianne Deng, Fatima Banine, Valerie Matagne, Matthew Frerking, Patricia Ohliger, Sarojini S Budden, Gregory A. Dissen, Jonathan Pevsner, Larry S ShermanAbstract:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MECP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. Direct MECP2 targets underlying RTT pathogenesis remain largely unknown. Here, we report that FXYD1, which encodes a transmembrane modulator of Na + ,K + -ATPase activity, is elevated in frontal cortex (FC) neurons of RTT patients and MECP2-null mice. Increasing neuronal FXDY1 expression is sufficient to reduce dendritic arborization and spine formation, hallmarks of RTT neuropathology. MECP2-null mouse cortical neurons have diminished Na + ,K + -ATPase activity, suggesting that aberrant FXYD1 expression contributes to abnormal neuronal activity in RTT. MECP2 represses Fxyd1 transcription through direct interactions with sequences in the Fxyd1 promoter that are methylated in FC neurons. FXYD1 is therefore a MECP2 target gene whose de-repression may directly contribute to RTT neuronal pathogenesis.