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Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2
Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Higher Education Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310543/ https://www.ncbi.nlm.nih.gov/pubmed/32851591 http://dx.doi.org/10.1007/s13238-020-00773-z |
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author | Chen, Xiaoying Han, Xu Blanchi, Bruno Guan, Wuqiang Ge, Weihong Yu, Yong-Chun Sun, Yi E. |
author_facet | Chen, Xiaoying Han, Xu Blanchi, Bruno Guan, Wuqiang Ge, Weihong Yu, Yong-Chun Sun, Yi E. |
author_sort | Chen, Xiaoying |
collection | PubMed |
description | Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2-deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13238-020-00773-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-8310543 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Higher Education Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-83105432021-08-12 Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2 Chen, Xiaoying Han, Xu Blanchi, Bruno Guan, Wuqiang Ge, Weihong Yu, Yong-Chun Sun, Yi E. Protein Cell Research Article Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2-deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13238-020-00773-z) contains supplementary material, which is available to authorized users. Higher Education Press 2020-08-27 2021-08 /pmc/articles/PMC8310543/ /pubmed/32851591 http://dx.doi.org/10.1007/s13238-020-00773-z Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Chen, Xiaoying Han, Xu Blanchi, Bruno Guan, Wuqiang Ge, Weihong Yu, Yong-Chun Sun, Yi E. Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2 |
title | Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2 |
title_full | Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2 |
title_fullStr | Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2 |
title_full_unstemmed | Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2 |
title_short | Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2 |
title_sort | graded and pan-neural disease phenotypes of rett syndrome linked with dosage of functional mecp2 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310543/ https://www.ncbi.nlm.nih.gov/pubmed/32851591 http://dx.doi.org/10.1007/s13238-020-00773-z |
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