MeCP2 is required for global heterochromatic and nucleolar changes during activity-dependent neuronal maturation

abstract Article history:Received 2 November 2010Revised 24 January 2011Accepted 11 March 2011Available online xxxxKeywords:MeCP2DNA methylationMaturationChromatinNucleoliNeuronalEpigeneticNeurodevelopmentalRett syndrome Mutations in MECP2, encoding methyl CpG binding protein 2, cause the neurodevelopmental disorder Rettsyndrome. MeCP2 is an abundant nuclear protein that binds to chromatin and modulates transcription inresponse toneuronal activity. Priorstudies ofMeCP2functionhave focused onspecificgene targets ofMeCP2,but a more global role for MeCP2 in neuronal nuclear maturation has remained unexplored. MeCP2 levelsincrease during postnatal brain development, coinciding with dynamic changes in neuronal chromatinarchitecture, particularly detectable as changes in size, number, and location of nucleoli and perinucleolarheterochromaticchromocenters.TodetermineapotentialroleforMeCP2inneuronalchromatinmaturationalchanges, we measured nucleoli and chromocenters in developing wild-type and Mecp2-deficient mousecortical sections, as well as mouse primary cortical neurons and a human neuronal cell line following inducedmaturation. Mecp2-deficient mouse neurons exhibited significant differences in nucleolar and chromocenternumber and size, as more abundant, smaller nucleoli in brain and primary neurons compared to wild-type,consistent with delayed neuronal nuclear maturation in the absence of MeCP2. Primary neurons increasedchromocenter size following depolarization in wild-type, but not Mecp2-deficient cultures. Wild-typeMECP2e1 over-expression in human SH-SY5Y cells was sufficient to induce significantly larger nucleoli, butnotaT158Mmutationofthemethyl-bindingdomain.Theseresultssuggestthat,inadditiontotheestablishedrole of MeCP2 in transcriptional regulation of specific target genes, the global chromatin-binding function ofMeCP2 is essential for activity-dependent global chromatin dynamics during postnatal neuronal maturation.© 2011 Elsevier Inc. All rights reserved.