title: Methyl-CpG binding protein 2 (MeCP2) localizes at the centrosome and is required for proper mitotic spindle organization.
abstract: Mutations in MECP2 cause a broad spectrum of neuropsychiatric disorders of which Rett syndrome represents the best defined condition. Both neuronal and non-neuronal functions of the methyl-binding protein underlie the related pathologies. Nowadays MeCP2 is recognized as a multifunctional protein that modulates its activity depending on its protein partners and posttranslational modifications. However, we are still missing a comprehensive understanding of all MeCP2 functions and their involvement in the related pathologies. The study of human mutations often offers the possibility of clarifying the functions of a protein. Therefore, we decided to characterize a novel MeCP2 phospho-isoform (Tyr-120) whose relevance was suggested by a Rett syndrome patient carrying a Y120D substitution possibly mimicking a constitutively phosphorylated state. Unexpectedly, we found MeCP2 and its Tyr-120 phospho-isoform enriched at the centrosome both in dividing and postmitotic cells. The molecular and functional connection of MeCP2 to the centrosome was further reinforced through cellular and biochemical approaches. We show that, similar to many centrosomal proteins, MeCP2 deficiency causes aberrant spindle geometry, prolonged mitosis, and defects in microtubule nucleation. Collectively, our data indicate a novel function of MeCP2 that might reconcile previous data regarding the role of MeCP2 in cell growth and cytoskeleton stability and that might be relevant to understand some aspects of MeCP2-related conditions. Furthermore, they link the Tyr-120 residue and its phosphorylation to cell division, prompting future studies on the relevance of Tyr-120 for cortical development.
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research, University of Insubria, 21052 Busto Arsizio, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bergo
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research, University of Insubria, 21052 Busto Arsizio, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Strollo
authors.affiliation: the Molecular Biotechnology Center, Department of Molecular Biotechnologies and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Gai
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research, University of Insubria, 21052 Busto Arsizio, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Barbiero
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research, University of Insubria, 21052 Busto Arsizio, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Stefanelli
authors.affiliation: the Department of Life Sciences, University of Milan, 20133 Milan, Italy, and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sertic
authors.affiliation: the San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Clementina
authors.initials: C
authors.lastname: Cobolli Gigli
authors.affiliation: the Molecular Biotechnology Center, Department of Molecular Biotechnologies and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Di Cunto
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research, University of Insubria, 21052 Busto Arsizio, Italy.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kilstrup-Nielsen
authors.affiliation: From the Department of Theoretical and Applied Sciences, Section of Biomedical Research, University of Insubria, 21052 Busto Arsizio, Italy, the San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy landsben@uninsubria.it.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Landsberger
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D020125:Mutation, Missense; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D015518:Rett Syndrome / Q000235:genetics
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D020033:Protein Isoforms
keywords: Cell Cycle; Cell Proliferation; Centrosome; MeCP2; Microtubule; Mitotic Spindle; Protein Phosphorylation