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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Mamounas, Laura
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University of Pennsylvania
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