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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4956225?pdf=render |
| _version_ | 1818268221987356672 |
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| author | Alison A Williams Vera J Mehler Christina Mueller Fernando Vonhoff Robin White Carsten Duch |
| author_facet | Alison A Williams Vera J Mehler Christina Mueller Fernando Vonhoff Robin White Carsten Duch |
| author_sort | Alison A Williams |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-12T20:35:03Z |
| format | Article |
| id | doaj.art-5a1e78d286854f4fa456ab5da7f71d14 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T20:35:03Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5a1e78d286854f4fa456ab5da7f71d142022-12-22T00:12:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01117e015963210.1371/journal.pone.0159632Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations.Alison A WilliamsVera J MehlerChristina MuellerFernando VonhoffRobin WhiteCarsten DuchMethyl-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.http://europepmc.org/articles/PMC4956225?pdf=render |
| spellingShingle | Alison A Williams Vera J Mehler Christina Mueller Fernando Vonhoff Robin White Carsten Duch Apoptotic Activity of MeCP2 Is Enhanced by C-Terminal Truncating Mutations. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC4956225?pdf=render |
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