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Neuronal activity-dependent regulation of MeCP2 (supplement)  

Mutations in MeCP2, a methyl-CpG-binding protein that functions as a regulator of gene expression, are a major cause of Rett Syndrome (RTT), an X-linked progressive autism spectrum disorder that is among the most common causes of profound cognitive impairment in girls and women. While the selective inactivation of MeCP2 in neurons has been suggested to be sufficient to confer a Rett-like phenotype in mice, the specific mechanisms by which the loss of MeCP2 function in postimitotic neurons contributes to RTT phenotypes remain unclear. We have identified serine 421 (S421) on MeCP2 as a site of neuronal activity-dependent phosphorylation that is induced selectively in the brain in response to physiological stimuli. Significantly, we have found that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription in both cultured neurons and slice preparations. To further explore the role of this regulatory mechanism in neural development in vivo, we have generated a knock-in mouse in which S421 of MeCP2 is mutated to an alanine residue (S421A KI), preventing the phosphorylation of MeCP2 at this site. Intriguingly, whereas the abrogation of MeCP2 S421 phosphorylation in vivo does not result in the motor and survival phenotypes seen with complete loss of MeCP2 expression, our preliminary studies have revealed a deficit in cortical inhibitory synaptic development in these S421A KI mice, suggesting that activity-dependent phosphorylation may be involved in a specific subset of MeCP2 functions relevant to the synaptic and cognitive defects observed in RTT. To begin to test this hypothesis and determine the extent to which MeCP2 functions as a general regulator of neuronal activity- dependent gene expression, we propose the following specific aims: (1) to investigate the contribution of MeCP2 S421 phosphorylation to experience-dependent synaptic development in vivo; (2) to assess the role of MeCP2 S421 phosphorylation in the regulation of activity-dependent neuronal gene expression; and (3) to characterize additional sites of activity-dependent MeCP2 phosphorylation. The proposed experiments should 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 $77,123.00
Current Award Period 2010-2011
Project Number 3R01NS048276-06S1
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 (supplement) (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 | $437,522.00 | 2010 | 2R01NS048276-06