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Science 31 October 2003:
Vol. 302. no. 5646, pp. 885 - 889
DOI: 10.1126/science.1086446
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Reports

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*

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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Genes & Dev. 18, 2315-2335
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The Cell-specific Expression of Endothelial Nitric-oxide Synthase: A ROLE FOR DNA METHYLATION.
Y. Chan, J. E. Fish, C. D'Abreo, S. Lin, G. B. Robb, A.-M. Teichert, F. Karantzoulis-Fegaras, A. Keightley, B. M. Steer, and P. A. Marsden (2004)
J. Biol. Chem. 279, 35087-35100
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X-Chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett syndrome and Mecp2-/+ mouse brain.
D. Braunschweig, T. Simcox, R. C. Samaco, and J. M. LaSalle (2004)
Hum. Mol. Genet. 13, 1275-1286
   Abstract »    Full Text »    PDF »
Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice.
S. Luikenhuis, E. Giacometti, C. F. Beard, and R. Jaenisch (2004)
PNAS 101, 6033-6038
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Mbd1 Is Recruited to both Methylated and Nonmethylated CpGs via Distinct DNA Binding Domains.
H. F. Jorgensen, I. Ben-Porath, and A. P. Bird (2004)
Mol. Cell. Biol. 24, 3387-3395
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The major form of MeCP2 has a novel N-terminus generated by alternative splicing.
S. Kriaucionis and A. Bird (2004)
Nucleic Acids Res. 32, 1818-1823
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NT-3 Replacement with Brain-Derived Neurotrophic Factor Redirects Vestibular Nerve Fibers to the Cochlea.
L. Tessarollo, V. Coppola, and B. Fritzsch (2004)
J. Neurosci. 24, 2575-2584
   Abstract »    Full Text »    PDF »
Reading the DNA Methylation Signal.
A. BIRD and D. MACLEOD (2004)
Cold Spring Harb Symp Quant Biol 69, 113-118
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DNA Methylation-Related Chromatin Remodeling in Activity-Dependent Bdnf Gene Regulation.
K. Martinowich, D. Hattori, H. Wu, S. Fouse, F. He, Y. Hu, G. Fan, and Y. E. Sun (2003)
Science 302, 890-893
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