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Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations
Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical hetero...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160375/ https://www.ncbi.nlm.nih.gov/pubmed/32243842 http://dx.doi.org/10.1016/j.stemcr.2020.03.007 |
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author | Anastasaki, Corina Wegscheid, Michelle L. Hartigan, Kelly Papke, Jason B. Kopp, Nathan D. Chen, Jiayang Cobb, Olivia Dougherty, Joseph D. Gutmann, David H. |
author_facet | Anastasaki, Corina Wegscheid, Michelle L. Hartigan, Kelly Papke, Jason B. Kopp, Nathan D. Chen, Jiayang Cobb, Olivia Dougherty, Joseph D. Gutmann, David H. |
author_sort | Anastasaki, Corina |
collection | PubMed |
description | Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability. |
format | Online Article Text |
id | pubmed-7160375 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-71603752020-04-22 Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations Anastasaki, Corina Wegscheid, Michelle L. Hartigan, Kelly Papke, Jason B. Kopp, Nathan D. Chen, Jiayang Cobb, Olivia Dougherty, Joseph D. Gutmann, David H. Stem Cell Reports Report Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability. Elsevier 2020-04-02 /pmc/articles/PMC7160375/ /pubmed/32243842 http://dx.doi.org/10.1016/j.stemcr.2020.03.007 Text en © 2020 The Authors 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 Anastasaki, Corina Wegscheid, Michelle L. Hartigan, Kelly Papke, Jason B. Kopp, Nathan D. Chen, Jiayang Cobb, Olivia Dougherty, Joseph D. Gutmann, David H. Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations |
title | Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations |
title_full | Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations |
title_fullStr | Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations |
title_full_unstemmed | Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations |
title_short | Human iPSC-Derived Neurons and Cerebral Organoids Establish Differential Effects of Germline NF1 Gene Mutations |
title_sort | human ipsc-derived neurons and cerebral organoids establish differential effects of germline nf1 gene mutations |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160375/ https://www.ncbi.nlm.nih.gov/pubmed/32243842 http://dx.doi.org/10.1016/j.stemcr.2020.03.007 |
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