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Published October 19, 2006 | Supplemental Material + Accepted Version
Journal Article Open

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

Abstract

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.

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.).

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Accepted Version - nihms184074.pdf

Supplemental Material - mmc1.pdf

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August 22, 2023
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