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Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development
Shank3 is a structural protein found predominantly at the postsynaptic density. Mutations in the SHANK3 gene have been associated with risk for autism spectrum disorder (ASD). We generated induced pluripotent stem cells (iPSCs) from control individuals and from human donors with ASD carrying microde...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822449/ https://www.ncbi.nlm.nih.gov/pubmed/28948968 http://dx.doi.org/10.1038/mp.2017.185 |
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author | Kathuria, A Nowosiad, P Jagasia, R Aigner, S Taylor, R D Andreae, L C Gatford, N J F Lucchesi, W Srivastava, D P Price, J |
author_facet | Kathuria, A Nowosiad, P Jagasia, R Aigner, S Taylor, R D Andreae, L C Gatford, N J F Lucchesi, W Srivastava, D P Price, J |
author_sort | Kathuria, A |
collection | PubMed |
description | Shank3 is a structural protein found predominantly at the postsynaptic density. Mutations in the SHANK3 gene have been associated with risk for autism spectrum disorder (ASD). We generated induced pluripotent stem cells (iPSCs) from control individuals and from human donors with ASD carrying microdeletions of SHANK3. In addition, we used Zinc finger nucleases to generate isogenic SHANK3 knockout human embryonic stem (ES) cell lines. We differentiated pluripotent cells into either cortical or olfactory placodal neurons. We show that patient-derived placodal neurons make fewer synapses than control cells. Moreover, patient-derived cells display a developmental phenotype: young postmitotic neurons have smaller cell bodies, more extensively branched neurites, and reduced motility compared with controls. These phenotypes were mimicked by SHANK3-edited ES cells and rescued by transduction with a Shank3 expression construct. This developmental phenotype is not observed in the same iPSC lines differentiated into cortical neurons. Therefore, we suggest that SHANK3 has a critical role in neuronal morphogenesis in placodal neurons and that early defects are associated with ASD-associated mutations. |
format | Online Article Text |
id | pubmed-5822449 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-58224492018-02-23 Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development Kathuria, A Nowosiad, P Jagasia, R Aigner, S Taylor, R D Andreae, L C Gatford, N J F Lucchesi, W Srivastava, D P Price, J Mol Psychiatry Original Article Shank3 is a structural protein found predominantly at the postsynaptic density. Mutations in the SHANK3 gene have been associated with risk for autism spectrum disorder (ASD). We generated induced pluripotent stem cells (iPSCs) from control individuals and from human donors with ASD carrying microdeletions of SHANK3. In addition, we used Zinc finger nucleases to generate isogenic SHANK3 knockout human embryonic stem (ES) cell lines. We differentiated pluripotent cells into either cortical or olfactory placodal neurons. We show that patient-derived placodal neurons make fewer synapses than control cells. Moreover, patient-derived cells display a developmental phenotype: young postmitotic neurons have smaller cell bodies, more extensively branched neurites, and reduced motility compared with controls. These phenotypes were mimicked by SHANK3-edited ES cells and rescued by transduction with a Shank3 expression construct. This developmental phenotype is not observed in the same iPSC lines differentiated into cortical neurons. Therefore, we suggest that SHANK3 has a critical role in neuronal morphogenesis in placodal neurons and that early defects are associated with ASD-associated mutations. Nature Publishing Group 2018 2017-09-26 /pmc/articles/PMC5822449/ /pubmed/28948968 http://dx.doi.org/10.1038/mp.2017.185 Text en Copyright © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Kathuria, A Nowosiad, P Jagasia, R Aigner, S Taylor, R D Andreae, L C Gatford, N J F Lucchesi, W Srivastava, D P Price, J Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development |
title | Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development |
title_full | Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development |
title_fullStr | Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development |
title_full_unstemmed | Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development |
title_short | Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development |
title_sort | stem cell-derived neurons from autistic individuals with shank3 mutation show morphogenetic abnormalities during early development |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822449/ https://www.ncbi.nlm.nih.gov/pubmed/28948968 http://dx.doi.org/10.1038/mp.2017.185 |
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