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Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation

Zhou, Zhaolan and Hong, Elizabeth J. and Cohen, Sonia and Zhao, Wen-ning and Ho, Hsin-yi Henry and Schmidt, Lauren and Chen, Wen G. and Lin, Yingxi and Savner, Erin and Griffith, Eric C. and Hu, Linda and Steen, Judith A. J. and Weitz, Charles J. and Greenberg, Michael E. (2006) Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation. Neuron, 52 (2). pp. 255-269. ISSN 0896-6273. PMCID PMC3962021. doi:10.1016/j.neuron.2006.09.037.

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Mutations or duplications in MECP2 cause Rett and Rett-like syndromes, neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autistic behaviors. MeCP2 is expressed in many mammalian tissues and functions as a global repressor of transcription; however, the molecular mechanisms by which MeCP2 dysfunction leads to the neural-specific phenotypes of RTT remain poorly understood. Here, we show that neuronal activity and subsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by a CaMKII-dependent mechanism. MeCP2 S421 phosphorylation is induced selectively in the brain in response to physiological stimuli. Significantly, we find that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation and that disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT.

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Additional Information:© 2007 Elsevier. Received: July 5, 2006; Revised: September 5, 2006; Accepted: September 29, 2006; Published: October 18, 2006. We are indebted to T. Soderling, T.K. Kim, J. Kornhauser, and M. Lin for valuable reagents and J. Li and S. Gygi for mass spectrometry analysis. We thank A.E. West, L. Jackson-Grusby, and members of the Greenberg laboratory for useful discussions and critical comments on the manuscript. M.E.G. acknowledges the generous support of the F.M. Kirby Foundation to the Children's Hospital Neurobiology Program. This work was supported by the Rett Syndrome Research Foundation (M.E.G.), National Institutes of Health grants (NS048276, M.E.G.; NS43491, C.J.W.), the NIH Medical Scientist Training Program (S.C.), the Damon Runyon Cancer Research Foundation (H.-y.H.H), the Fannie and John Hertz Foundation (E.J.H.), and the Helen Hay Whitney Foundation (E.C.G., Z.Z.).
Funding AgencyGrant Number
F. M. Kirby FoundationUNSPECIFIED
Rett Syndrome Research FoundationUNSPECIFIED
NIH Medical Scientist Training ProgramUNSPECIFIED
Damon Runyon Cancer Research FoundationUNSPECIFIED
Fannie and John Hertz FoundationUNSPECIFIED
Helen Hay Whitney FoundationUNSPECIFIED
Issue or Number:2
PubMed Central ID:PMC3962021
Record Number:CaltechAUTHORS:20151005-165128774
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Official Citation:Zhaolan Zhou, Elizabeth J. Hong, Sonia Cohen, Wen-ning Zhao, Hsin-yi Henry Ho, Lauren Schmidt, Wen G. Chen, Yingxi Lin, Erin Savner, Eric C. Griffith, Linda Hu, Judith A.J. Steen, Charles J. Weitz, Michael E. Greenberg, Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation, Neuron, Volume 52, Issue 2, 19 October 2006, Pages 255-269, ISSN 0896-6273, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:60790
Deposited By: George Porter
Deposited On:06 Oct 2015 21:57
Last Modified:10 Nov 2021 22:39

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