title: MeCP2 is required for global heterochromatic and nucleolar changes during activity-dependent neuronal maturation.
abstract: Mutations in MECP2, encoding methyl CpG binding protein 2, cause the neurodevelopmental disorder Rett syndrome. MeCP2 is an abundant nuclear protein that binds to chromatin and modulates transcription in response to neuronal activity. Prior studies of MeCP2 function have focused on specific gene targets of MeCP2, but a more global role for MeCP2 in neuronal nuclear maturation has remained unexplored. MeCP2 levels increase during postnatal brain development, coinciding with dynamic changes in neuronal chromatin architecture, particularly detectable as changes in size, number, and location of nucleoli and perinucleolar heterochromatic chromocenters. To determine a potential role for MeCP2 in neuronal chromatin maturational changes, we measured nucleoli and chromocenters in developing wild-type and Mecp2-deficient mouse cortical sections, as well as mouse primary cortical neurons and a human neuronal cell line following induced maturation. Mecp2-deficient mouse neurons exhibited significant differences in nucleolar and chromocenter number 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 increased chromocenter size following depolarization in wild-type, but not Mecp2-deficient cultures. Wild-type MECP2e1 over-expression in human SH-SY5Y cells was sufficient to induce significantly larger nucleoli, but not a T158M mutation of the methyl-binding domain. These results suggest that, in addition to the established role of MeCP2 in transcriptional regulation of specific target genes, the global chromatin-binding function of MeCP2 is essential for activity-dependent global chromatin dynamics during postnatal neuronal maturation.
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, Genome Center, and MIND Institute, University of California, Davis, CA 95616, USA.
authors.forename: Malaika K
authors.initials: MK
authors.lastname: Singleton
authors.forename: Michael L
authors.initials: ML
authors.lastname: Gonzales
authors.forename: Karen N
authors.initials: KN
authors.lastname: Leung
authors.forename: Dag H
authors.initials: DH
authors.lastname: Yasui
authors.forename: Diane I
authors.initials: DI
authors.lastname: Schroeder
authors.forename: Keith
authors.initials: K
authors.lastname: Dunaway
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D005260:Female; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*
chemical_list: D006570:Heterochromatin; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2