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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

In vivo function of neuronal activity-induced MeCP2 phosphorylation

Principal Investigator

Principal Investigator

Chang, Qiang

Description

Description

MeCP2 (methyl-CpG binding protein 2) functions as a molecular linker between DNA methylation, chromatin remodeling, and transcription regulation. Mutations in the X-linked human MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder that predominantly affects females. To understand the molecular mechanism of RTT, it is important to study how MeCP2 dynamically regulates gene transcription and to reveal the physiological significance of such regulation. Recent biochemical analysis has identified 8 phosphorylation sites on the MeCP2 protein. Among these, serine 80 (S80) is phosphorylated in resting neurons but dephosphorylated in active neurons, whereas serine 421 (S421) is dephosphorylated in resting neurons but phosphorylated in active neurons. Differential phosphorylation of MeCP2 in response to neuronal activity may serve as a molecular switch in dynamically modulating neuronal gene expression, leading to important consequences in development and function of the adult brain. To test this hypothesis in vivo, several novel Mecp2 knock-in alleles carrying point mutations that either abolish or mimic phosphorylation at S80 and S421 on the MeCP2 protein have been generated. As a part of a long-term goal to understand the dynamic role of MeCP2 in DNA methylation-dependent epigenetic regulation of mammalian brain development and functions, this project will study the effects of manipulating MeCP2 phosphorylation on animal behavior, study the effects of manipulating MeCP2 phosphorylation on adult neurogenesis, and study how MeCP2 phosphorylation regulates its binding to the brain-derived neurotrophic factor (Bdnf) promoter, remodels chromatin and subsequently alters BDNF expression and neuronal activity. Together, these experiments will provide insights into the central role of neuronal activity-induced differential phosphorylation of MeCP2 in regulating neuronal gene expression and its functional significance in neuronal development and animal behavior.

Funder

Funder

National Institutes of Health

Fiscal Year Funding

Fiscal Year Funding

292721

Current Award Period

Current Award Period

2010-2015

Strategic Plan Question

Strategic Plan Question

Question 3: What Caused This To Happen And Can This Be Prevented?

Strategic Plan Objective

Strategic Plan Objective

Green dot: Objective has greater than or equal to the recommended funding. 3SJ. Support at least three studies that focus on the role of epigenetics in the etiology of ASD, including studies that include assays to measure DNA methylations and histone modifications and those exploring how exposures may act on maternal or paternal genomes via epigenetic mechanisms to alter gene expression, by 2012. IACC Recommended Budget: $20,000,000 over 5 years.

Project Link

Project Link

In vivo function of neuronal activity-induced MeCP2 phosphorylation (External web link)

Institution

Institution

University of Wisconsin - Madison

State/Country

State/Country

Wisconsin

Project Number

Project Number

5R01HD064743-02

Federal or Private?

Federal or Private?

Federal

Received ARRA Funding?

Received ARRA Funding?

No

History/Related Projects

History/Related Projects

In vivo function of neuronal activity-induced MeCP2 phosphorylation | 292721 | 2012 | 5R01HD064743-03

 
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