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Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations

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 a...

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Autores principales: Williams, Alison A., Mehler, Vera J., Mueller, Christina, Vonhoff, Fernando, White, Robin, Duch, Carsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956225/
https://www.ncbi.nlm.nih.gov/pubmed/27442528
http://dx.doi.org/10.1371/journal.pone.0159632
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author Williams, Alison A.
Mehler, Vera J.
Mueller, Christina
Vonhoff, Fernando
White, Robin
Duch, Carsten
author_facet Williams, Alison A.
Mehler, Vera J.
Mueller, Christina
Vonhoff, Fernando
White, Robin
Duch, Carsten
author_sort Williams, Alison A.
collection PubMed
description 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.
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spelling pubmed-49562252016-08-08 Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations Williams, Alison A. Mehler, Vera J. Mueller, Christina Vonhoff, Fernando White, Robin Duch, Carsten PLoS One Research Article 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. Public Library of Science 2016-07-21 /pmc/articles/PMC4956225/ /pubmed/27442528 http://dx.doi.org/10.1371/journal.pone.0159632 Text en © 2016 Williams et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Williams, Alison A.
Mehler, Vera J.
Mueller, Christina
Vonhoff, Fernando
White, Robin
Duch, Carsten
Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations
title Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations
title_full Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations
title_fullStr Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations
title_full_unstemmed Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations
title_short Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations
title_sort apoptotic activity of mecp2 is enhanced by c-terminal truncating mutations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956225/
https://www.ncbi.nlm.nih.gov/pubmed/27442528
http://dx.doi.org/10.1371/journal.pone.0159632
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