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

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

Research output: Contribution to journalArticle

598 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)255-269
Number of pages15
JournalNeuron
Volume52
Issue number2
DOIs
StatePublished - Oct 19 2006
Externally publishedYes

Keywords

  • DEVBIO
  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

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    Zhou, Z., Hong, E. J., Cohen, S., Zhao, W. N., Ho, H-Y. H., Schmidt, L., Chen, W. G., Lin, Y., Savner, E., Griffith, E. C., Hu, L., Steen, J. A. J., Weitz, C. J., & Greenberg, M. E. (2006). Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation. Neuron, 52(2), 255-269. https://doi.org/10.1016/j.neuron.2006.09.037