Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2.
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.
Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Wen G
WG
Chen
Qiang
Q
Chang
Yingxi
Y
Lin
Alexander
A
Meissner
Anne E
AE
West
Eric C
EC
Griffith
Rudolf
R
Jaenisch
Michael E
ME
Greenberg
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone; D003001:Cloning, Molecular; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D051381:Rats; D012097:Repressor Proteins; D015518:Rett Syndrome / Q000235:genetics; D014158:Transcription, Genetic
D019208:Brain-Derived Neurotrophic Factor; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; C497393:Mecp2 protein, mouse; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; D011189:Potassium Chloride; D002118:Calcium