Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation.
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.
Zhou
Zhaolan
Z
Neurobiology Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hong
Elizabeth J
EJ
Cohen
Sonia
S
Zhao
Wen-Ning
WN
Ho
Hsin-Yi Henry
HY
Schmidt
Lauren
L
Chen
Wen G
WG
Lin
Yingxi
Y
Savner
Erin
E
Griffith
Eric C
EC
Hu
Linda
L
Steen
Judith A J
JA
Weitz
Charles J
CJ
Greenberg
Michael E
ME
D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D020013:Calcium Signaling / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D009434:Neural Pathways / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology; D009924:Organ Culture Techniques; D009928:Organ Specificity / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012694:Serine / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D012694:Serine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases