title: Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations.
abstract: Methyl-CpG binding protein 2 (MeCP2) is a widely abundant, multifunctional protein most highly expressed in post-mitotic neurons. Mutations causing Rett syndrome and related neurodevelopmental disorders have been identified along the entire MECP2 locus, but symptoms vary depending on mutation type and location. C-terminal mutations are prevalent, but little is known about the function of the MeCP2 C-terminus. We employ the genetic efficiency of Drosophila to provide evidence that expression of p.Arg294* (more commonly identified as R294X), a human MECP2 E2 mutant allele causing truncation of the C-terminal domains, promotes apoptosis of identified neurons in vivo. We confirm this novel finding in HEK293T cells and then use Drosophila to map the region critical for neuronal apoptosis to a small sequence at the end of the C-terminal domain. In vitro studies in mammalian systems previously indicated a role of the MeCP2 E2 isoform in apoptosis, which is facilitated by phosphorylation at serine 80 (S80) and decreased by interactions with the forkhead protein FoxG1. We confirm the roles of S80 phosphorylation and forkhead domain transcription factors in affecting MeCP2-induced apoptosis in Drosophila in vivo, thus indicating mechanistic conservation between flies and mammalian cells. Our findings are consistent with a model in which C- and N-terminal interactions are required for healthy function of MeCP2.
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America.|Institute of Zoology- Neurobiology, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Alison A
authors.identifier: http://orcid.org/0000-0002-7313-2771
authors.initials: AA
authors.lastname: Williams
authors.affiliation: Institute of Zoology- Neurobiology, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Mehler
authors.affiliation: Institute of Physiology, University Medical Center, Mainz, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Mueller
authors.affiliation: Molecular, Cellular, and Developmental Biology Department, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Fernando
authors.initials: F
authors.lastname: Vonhoff
authors.affiliation: Institute of Physiology, University Medical Center, Mainz, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: White
authors.affiliation: Institute of Zoology- Neurobiology, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Duch
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry* / Q000235:genetics*; D008954:Models, Biological; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D000072417:Protein Domains; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D029721:Drosophila Proteins; D051783:Methyl-CpG-Binding Protein 2; D050505:Mutant Proteins; D014157:Transcription Factors; C074838:slp1 protein, Drosophila; D010768:Phosphoserine; D020169:Caspases