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PMID: 17046689 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation.

Neuron ·Vol. 52 ·No. 2 ·2006-10-19 ·Pages 255-69

Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, Lin Y, Savner E, Griffith EC, Hu L, Steen JA, Weitz CJ, Greenberg ME

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.

MeSH Terms
Animals Brain/cytology,growth & development,metabolism Brain-Derived Neurotrophic Factor/biosynthesis,genetics Calcium Signaling/physiology Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Differentiation/physiology Dendritic Spines/metabolism,ultrastructure Gene Expression Regulation, Developmental/physiology Methyl-CpG-Binding Protein 2/genetics,metabolism Neural Pathways/cytology,growth & development,metabolism Neuronal Plasticity/physiology Organ Culture Techniques Organ Specificity/physiology Phosphorylation Rats Rett Syndrome/genetics,metabolism,physiopathology Serine/metabolism Synaptic Transmission/physiology
Chemicals
Brain-Derived Neurotrophic Factor Mecp2 protein, rat Methyl-CpG-Binding Protein 2 Serine Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calcium-Calmodulin-Dependent Protein Kinases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Zhou Zhaolan
Neurobiology Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hong Elizabeth J
Cohen Sonia
Zhao Wen-Ning
Ho Hsin-Yi Henry
Schmidt Lauren
Chen Wen G
Lin Yingxi
Savner Erin
Griffith Eric C
Hu Linda
Steen Judith A J
Weitz Charles J
Greenberg Michael E
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
0896-6273
DOI
10.1016/j.neuron.2006.09.037
Published
2006-10-19
Pages
255-69
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC3962021
Subset
IM
Grants
NINDS NIH HHS · R00 NS058391 · United States
NINDS NIH HHS · R00 NS058391-04 · United States
NINDS NIH HHS · K99 NS058391-02 · United States
NINDS NIH HHS · R01 NS043491 · United States
NINDS NIH HHS · NS43491 · United States
NIGMS NIH HHS · T32 GM007753 · United States
NINDS NIH HHS · R00 NS058391-03 · United States
NINDS NIH HHS · K99 NS058391 · United States
NINDS NIH HHS · NS048276 · United States
NINDS NIH HHS · R01 NS048276 · United States
NINDS NIH HHS · R00 NS058391-05 · United States
NINDS NIH HHS · K99 NS058391-01 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2006.09.037 PMC Full Text View journal details
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