Rett Syndrome (RTT) is one of the Autism Spectrum Disorders (ASDs) with a known genetic cause and represents one of the leading causes of mental retardation in fernales. RTT is caused by mutations in the Xlinked gene encoding methyl-CpG-binding protein 2 (MeCP2). The onset of RTT after normal early postnatal development and the precipitous loss of learned language and motor skills suggest a hypothesis that the clinical features of RTT result from a failure of activity-dependent neuronal development Recently we discovered that MeCP2 supresses Brain Derived Neurotrophic Factor (BDNF) expression in the absence of neuronal stimuli. In the presence of stimuli, MeCP2 undergpesCaMKlI-mediated phosphorylation and releases repression to Bdnf We have characterized a phosphorylatioii site (S421) on MeCP2 that selectively senses neuronal activity to control Bdnf transcription, modulate dendritic outgi-ovrth and spine maturation. Our findings challenged the canonical view of MeCP2 as a global transcriptiorial repressdrand implicated MeCP2 in the molecular program controlling experience-dependent neuronal development. To uiiderstand the molecular mechanisms by which activity-dependent phosphoryaltion of MeCP2 modulates its functioh and to assess the role of MeCP2 phosphoryailtion on neuronal development in vivo, we have identified a second phosphorylation event on MeCP2 at Threonine 158 (T158) and developed a knock-in mouse model in which T158 is mutated to alanine during the mentcred phase of this award (K99), Notably, T158 is located at the methyl-CpG binding domain of MeCP2 and is one of the most frequently mutated residue found in RTT patients. Thus, we plan to continue our research as initially proposed. The updated specific aims are 1) To characterize the nature of T158 phosphorylation and the mechanisms by which MeCP2 function is regulated by T158 phosphorylation;2) To characterize the function of MeCP2 T158 phosphorylation in neuronal development by analyzing the molecular and cellular phenotypes of T158A knock-in mouse model.
It is our hope that the proposed experiments will provide a better understanding of MeCP2 function, give insight into the mechanisms of activity-dependent gene expression and neuronal development, and provide new opportunities for the development of therapeutic strategies to alleviate RTT pathology.
|Zhou, Ailing; Han, Song; Zhou, Zhaolan Joe (2017) Molecular and genetic insights into an infantile epileptic encephalopathy - CDKL5 disorder. Front Biol (Beijing) 12:1-6|
|Wang, I-Ting J; Reyes, Arith-Ruth S; Zhou, Zhaolan (2013) Neuronal morphology in MeCP2 mouse models is intrinsically variable and depends on age, cell type, and Mecp2 mutation. Neurobiol Dis 58:3-12|
|Zhao, Ying-Tao; Goffin, Darren; Johnson, Brian S et al. (2013) Loss of MeCP2 function is associated with distinct gene expression changes in the striatum. Neurobiol Dis 59:257-66|
|Wang, I-Ting Judy; Allen, Megan; Goffin, Darren et al. (2012) Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice. Proc Natl Acad Sci U S A 109:21516-21|
|Goffin, Darren; Zhou, Zhaolan Joe (2012) The neural circuit basis of Rett syndrome. Front Biol (Beijing) 7:428-435|
|Goffin, Darren; Allen, Megan; Zhang, Le et al. (2011) Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat Neurosci 15:274-83|
|Cohen, Sonia; Gabel, Harrison W; Hemberg, Martin et al. (2011) Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72:72-85|
|Bracaglia, Giorgia; Conca, Barbara; Bergo, Anna et al. (2009) Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis. EMBO Rep 10:1327-33|
|Wood, Lydia; Gray, Noah W; Zhou, Zhaolan et al. (2009) 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 29:12440-8|
|Cukier, Holly N; Perez, Alma M; Collins, Ann L et al. (2008) Genetic modifiers of MeCP2 function in Drosophila. PLoS Genet 4:e1000179|
Showing the most recent 10 out of 11 publications