Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses
Darren Goffin, Megan Allen, Le Zhang, Maria Amorim, I-Ting Judy Wang, Arith-Ruth S Reyes, Amy Mercado-Berton, Caroline Ong, Sonia Cohen, Linda Hu, Julie A Blendy, Gregory C Carlson, Steve J Siegel, Michael E Greenberg, Zhaolan Zhou, Darren Goffin, Megan Allen, Le Zhang, Maria Amorim, I-Ting Judy Wang, Arith-Ruth S Reyes, Amy Mercado-Berton, Caroline Ong, Sonia Cohen, Linda Hu, Julie A Blendy, Gregory C Carlson, Steve J Siegel, Michael E Greenberg, Zhaolan Zhou
Abstract
Mutations in the MECP2 gene cause the autism spectrum disorder Rett syndrome (RTT). One of the most common MeCP2 mutations associated with RTT occurs at threonine 158, converting it to methionine (T158M) or alanine (T158A). To understand the role of T158 mutations in the pathogenesis of RTT, we generated knockin mice that recapitulate the MeCP2 T158A mutation. We found a causal role for T158A mutation in the development of RTT-like phenotypes, including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those present in Mecp2 null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. The age-dependent development of event-related neuronal responses was disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials (ERPs) may serve as a biomarker for RTT and treatment evaluation.
Figures
References
- Amir RE, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–188.
- Bienvenu T, Chelly J. Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized. Nat Rev Genet. 2006;7:415–426.
- Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56:422–437.
- Chen RZ, Akbarian S, Tudor M, Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 2001;27:327–331.
- Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 2001;27:322–326.
- Shahbazian M, et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron. 2002;35:243–254.
- Collins AL, et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet. 2004;13:2679–2689.
- Pelka GJ. Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice. Brain. 2006;129:887–898.
- Kerr B, Alvarez-Saavedra M, Sáez MA, Saona A, Young JI. Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice. Hum Mol Genet. 2008;17:1707–1717.
- Samaco RC, et al. A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum Mol Genet. 2008;17:1718–1727.
- Jentarra GM, et al. Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation. BMC Neurosci. 2010;11:19.
- Guy J, Gan J, Selfridge J, Cobb S, Bird A. Reversal of neurological defects in a mouse model of Rett syndrome. Science. 2007;315:1143–1147.
- Lioy DT, et al. A role for glia in the progression of Rett’s syndrome. Nature. 2011 doi: 10.1038/nature10214.
- Ho KL, et al. MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol Cell. 2008;29:525–531.
- Dani VS, et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc Natl Acad Sci USA. 2005;102:12560–12565.
- Dani VS, Nelson SB. Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome. J Neurosci. 2009;29:11263–11270.
- Wood L, Gray NW, Zhou Z, Greenberg ME, Shepherd GMG. Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in an RNA interference model of methyl-CpG-binding protein 2 deficiency. J Neurosci. 2009;29:12440–12448.
- Uhlhaas PJ, Singer W. Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010;11:100–113.
- Gandal MJ, Edgar JC, Klook K, Siegel SJ. Gamma synchrony: Towards a translational biomarker for the treatment-resistant symptoms of schizophrenia. Neuropharmacology. 2011 doi: 10.1016/j.neuropharm.2011.02.007.
- Roberts TPL, et al. MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism. Autism Res. 2010;3:8–18.
- Gandal MJ, et al. Validating γ oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry. 2010;68:1100–1106.
- Chao HT, et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature. 2010;468:263–269.
- D’Cruz JA, et al. Alterations of cortical and hippocampal EEG activity in MeCP2-deficient mice. Neurobiol Dis. 2010;38:8–16.
- Bader GG, Witt-Engerström I, Hagberg B. Neurophysiological findings in the Rett syndrome, II: Visual and auditory brainstem, middle and late evoked responses. Brain Dev. 1989;11:110–114.
- Stauder JEA, Smeets EEJ, van Mil SGM, Curfs LGM. The development of visual- and auditory processing in Rett syndrome: an ERP study. Brain Dev. 2006;28:487–494.
- Vacca M, et al. MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region. Brain Dev. 2001;23 (Suppl 1):S246–50.
- Schanen C, et al. Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. Am J Med Genet A. 2004;126A:129–140.
- Armstrong DD. Neuropathology of Rett syndrome. J Child Neurol. 2005;20:747–753.
- Feng G, et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron. 2000;28:41–51.
- Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum Mol Genet. 2002;11:115–124.
- Skene PJ, et al. Neuronal MeCP2 Is Expressed at Near Histone-Octamer Levels and Globally Alters the Chromatin State. Mol Cell. 2010;37:457–468.
- Chahrour M, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320:1224–1229.
- Nan X, Tate P, Li E, Bird A. DNA methylation specifies chromosomal localization of MeCP2. Mol Cell Biol. 1996;16:414–421.
- Nuber UA, et al. Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum Mol Genet. 2005;14:2247–2256.
- Jones PL, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19:187–191.
- Nan X, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393:386–389.
- Uhlhaas PJ, Pipa G, Neuenschwander S, Wibral M, Singer W. A new look at gamma? High- (>60 Hz) γ-band activity in cortical networks: function, mechanisms and impairment. Prog Biophys Mol Biol. 2011;105:14–28.
- Tallon-Baudry C, Bertrand O. Oscillatory gamma activity in humans and its role in object representation. Trends Cogn Sci (Regul Ed) 1999;3:151–162.
- Buzsáki G, Draguhn A. Neuronal oscillations in cortical networks. Science. 2004;304:1926–1929.
- Winterer G, et al. Schizophrenia: reduced signal-to-noise ratio and impaired phase-locking during information processing. Clin Neurophysiol. 2000;111:837–849.
- Foster BA, Coffey HA, Morin MJ, Rastinejad F. Pharmacological rescue of mutant p53 conformation and function. Science. 1999;286:2507–2510.
- Kishi N, Macklis JD. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci. 2004;27:306–321.
- Uhlhaas PJ, Singer W. Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology. Neuron. 2006;52:155–168.
- Ben-Ari Y. Developing networks play a similar melody. Trends Neurosci. 2001;24:353–360.
- Goffin D, et al. Dopamine-dependent tuning of striatal inhibitory synaptogenesis. J Neurosci. 2010;30:2935–2950.
- Zhou Z, et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron. 2006;52:255–269.
- Liao WL, et al. Modular patterning of structure and function of the striatum by retinoid receptor signaling. Proc Natl Acad Sci USA. 2008;105:6765–6770.
- Canolty RT, et al. High gamma power is phase-locked to theta oscillations in human neocortex. Science. 2006;313:1626–1628.
- Hardisty-Hughes RE, Parker A, Brown SDM. A hearing and vestibular phenotyping pipeline to identify mouse mutants with hearing impairment. Nat Protoc. 2010;5:177–190.
Source: PubMed