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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
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.
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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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