Project Detail
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Office of Autism Research Coordination (OARC) logo

Neuronal activity-dependent regulation of MeCP2  

Rett Syndrome is a progressive autistic disorder that is among the most common causes of profound cognitive impairment in girls and women. In an effort to gain insight into the underlying molecular basis of the disorder, the proposed study will seek to explore the hypothesis that this autistic disorder reflects a defect in the dynamic regulation of genes in the central nervous system. Mutations in MeCP2, a methyl-CpG-binding protein that functions as a regulator of gene expression, are a major cause of Rett Syndrome (RTT). While the selective inactivation of MeCP2 in neurons can result in a Rett-like phenotype in mice, the specific mechanisms by which the loss of MeCP2 function in neurons contributes to RTT phenotypes remain unclear. We have identified the amino acid at position 421 on MeCP2, serine 421 (S421), as a site of neuronal activity-dependent phosphorylation that is induced selectively in the brain in response to physiological stimuli. Significantly, when MeCP2 becomes phosphorylated on serine 421, the protein regulates dendritic patterning, spine morphogenesis, and protein transcription in both cultured neurons and brain slice preparations. To further explore the role of this regulatory mechanism in neural development in vivo, the researchers generated a genetically engineered mouse in which S421 of MeCP2 is mutated to an alanine residue (S421A KI), preventing the phosphorylation of MeCP2 at this site. The researchers hypothesize mice expressing this non-phosphorylated MeCP2 will have specific synaptic and cognitive defects. The proposed experiments will provide a better understanding of MeCP2 function, give insight into the mechanisms of activity-dependent gene expression, and provide new opportunities for the development of therapeutic strategies to alleviate RTT pathology. Project Status
NEW

2010

Funder National Institutes of Health
Fiscal Year Funding $437,522.00
Current Award Period 2010-2015
Project Number 2R01NS048276-06
Principal Investigator Greenberg, Michael
Received ARRA Funding? No
Strategic Plan Question Question 2: How Can I Understand What Is Happening? (Biology)
Subcategory Molecular Pathways
Strategic Plan Objective Green dot: Objective has greater than or equal to the recommended funding. 2SD. Launch three studies that target improved understanding of the underlying biological pathways of genetic conditions related to autism (e.g. Fragile X, Rett syndrome, tuberous sclerosis complex) and how these conditions inform risk assessment and individualized intervention by 2012. IACC Recommended Budget: $9,000,000 over 5 years.
Federal or Private? Federal
Institution Harvard Medical School
State/Country Massachusetts
Web Link 1 Neuronal activity-dependent regulation of MeCP2 (External web link)
Web Link 2 No URL available.
Web Link 3 No URL available.
New! History/Related Projects Neuronal activity-dependent regulation of MeCP2 (supplement) | $77,123.00 | 2010 | 3R01NS048276-06S1