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Interagency Autism Coordinating Committee (IACC)
Autism Research Database
Office of Autism Research Coordination (OARC)
 
Project Element Element Description

Project Title

Project Title

Neuronal activity-dependent regulation of MeCP2

Principal Investigator

Principal Investigator

Greenberg, Michael

Description

Description

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.

Funder

Funder

National Institutes of Health

Fiscal Year Funding

Fiscal Year Funding

426857

Current Award Period

Current Award Period

2010-2015

Strategic Plan Question

Strategic Plan Question

Question 2: How Can I Understand What Is Happening?

Strategic Plan Objective

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.

Project Link

Project Link

Neuronal activity-dependent regulation of MeCP2 (External web link)

Institution

Institution

Harvard Medical School

State/Country

State/Country

Massachusetts

Project Number

Project Number

5R01NS048276-07

Federal or Private?

Federal or Private?

Federal

Received ARRA Funding?

Received ARRA Funding?

No

History/Related Projects

History/Related Projects

N/A

 
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