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Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence
To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular pro...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995366/ https://www.ncbi.nlm.nih.gov/pubmed/29742391 http://dx.doi.org/10.1016/j.stemcr.2018.04.001 |
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author | Ohashi, Minori Korsakova, Elena Allen, Denise Lee, Peiyee Fu, Kai Vargas, Benni S. Cinkornpumin, Jessica Salas, Carlos Park, Jenny C. Germanguz, Igal Langerman, Justin Chronis, Contantinos Kuoy, Edward Tran, Stephen Xiao, Xinshu Pellegrini, Matteo Plath, Kathrin Lowry, William E. |
author_facet | Ohashi, Minori Korsakova, Elena Allen, Denise Lee, Peiyee Fu, Kai Vargas, Benni S. Cinkornpumin, Jessica Salas, Carlos Park, Jenny C. Germanguz, Igal Langerman, Justin Chronis, Contantinos Kuoy, Edward Tran, Stephen Xiao, Xinshu Pellegrini, Matteo Plath, Kathrin Lowry, William E. |
author_sort | Ohashi, Minori |
collection | PubMed |
description | To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder. |
format | Online Article Text |
id | pubmed-5995366 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-59953662018-06-12 Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence Ohashi, Minori Korsakova, Elena Allen, Denise Lee, Peiyee Fu, Kai Vargas, Benni S. Cinkornpumin, Jessica Salas, Carlos Park, Jenny C. Germanguz, Igal Langerman, Justin Chronis, Contantinos Kuoy, Edward Tran, Stephen Xiao, Xinshu Pellegrini, Matteo Plath, Kathrin Lowry, William E. Stem Cell Reports Report To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder. Elsevier 2018-05-08 /pmc/articles/PMC5995366/ /pubmed/29742391 http://dx.doi.org/10.1016/j.stemcr.2018.04.001 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Report Ohashi, Minori Korsakova, Elena Allen, Denise Lee, Peiyee Fu, Kai Vargas, Benni S. Cinkornpumin, Jessica Salas, Carlos Park, Jenny C. Germanguz, Igal Langerman, Justin Chronis, Contantinos Kuoy, Edward Tran, Stephen Xiao, Xinshu Pellegrini, Matteo Plath, Kathrin Lowry, William E. Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence |
title | Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence |
title_full | Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence |
title_fullStr | Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence |
title_full_unstemmed | Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence |
title_short | Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence |
title_sort | loss of mecp2 leads to activation of p53 and neuronal senescence |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995366/ https://www.ncbi.nlm.nih.gov/pubmed/29742391 http://dx.doi.org/10.1016/j.stemcr.2018.04.001 |
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