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Science 302 (5646): 885-889

Copyright © 2003 by the American Association for the Advancement of Science

Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2

Wen G. Chen,1,2 Qiang Chang,3 Yingxi Lin,1 Alexander Meissner,3,4 Anne E. West,1 Eric C. Griffith,1 Rudolf Jaenisch,3,4 Michael E. Greenberg1,2*

Abstract: Mutations in MeCP2, which encodes a protein that has been proposed to function as a global transcriptional repressor, are the cause of Rett syndrome (RT T), an X-linked progressive neurological disorder. Although the selective inactivation of MeCP2 in neurons is sufficient to confer a Rett-like phenotype in mice, the specific functions of MeCP2 in postmitotic neurons are not known. We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene. Membrane depolarization triggers the calcium-dependent phosphorylation and release of MeCP2 from BDNF promoter III, thereby facilitating transcription. These studies indicate that MeCP2 plays a key role in the control of neuronal activity–dependent gene regulation and suggest that the deregulation of this process may underlie the pathology of RT T.

1 Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2 Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
3 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
4 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

* To whom correspondence should be addressed. E-mail: Michael.Greenberg{at}tch.harvard.edu


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C. K. Hwang, K. Y. Song, C. S. Kim, H. S. Choi, X.-H. Guo, P.-Y. Law, L.-N. Wei, and H. H. Loh (2007)
Mol. Cell. Biol. 27, 4720-4736
   Abstract »    Full Text »    PDF »
A Role for Transcriptional Repressor Methyl-CpG-Binding Protein 2 and Plasticity-Related Gene Serum- and Glucocorticoid-Inducible Kinase 1 in the Induction of Inflammatory Pain States.
S. M. Geranton, C. Morenilla-Palao, and S. P. Hunt (2007)
J. Neurosci. 27, 6163-6173
   Abstract »    Full Text »    PDF »
Mbd2 Contributes to DNA Methylation-Directed Repression of the Xist Gene.
H. Barr, A. Hermann, J. Berger, H.-H. Tsai, K. Adie, A. Prokhortchouk, B. Hendrich, and A. Bird (2007)
Mol. Cell. Biol. 27, 3750-3757
   Abstract »    Full Text »    PDF »
Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation.
X. Nan, J. Hou, A. Maclean, J. Nasir, M. J. Lafuente, X. Shu, S. Kriaucionis, and A. Bird (2007)
PNAS 104, 2709-2714
   Abstract »    Full Text »    PDF »
The Transcription Factor Nerve Growth Factor-Inducible Protein A Mediates Epigenetic Programming: Altering Epigenetic Marks by Immediate-Early Genes.
I. C. G. Weaver, A. C. D'Alessio, S. E. Brown, I. C. Hellstrom, S. Dymov, S. Sharma, M. Szyf, and M. J. Meaney (2007)
J. Neurosci. 27, 1756-1768
   Abstract »    Full Text »    PDF »
Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2.
E. Giacometti, S. Luikenhuis, C. Beard, and R. Jaenisch (2007)
PNAS 104, 1931-1936
   Abstract »    Full Text »    PDF »
Chimeric DNA methyltransferases target DNA methylation to specific DNA sequences and repress expression of target genes.
F. Li, M. Papworth, M. Minczuk, C. Rohde, Y. Zhang, S. Ragozin, and A. Jeltsch (2007)
Nucleic Acids Res. 35, 100-112
   Abstract »    Full Text »    PDF »

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