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Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models
Exonic deletions in NRXN1 have been associated with several neurodevelopmental disorders, including autism, schizophrenia and developmental delay. However, the molecular mechanism by which NRXN1 deletions impact neurodevelopment remains unclear. Here we used human induced pluripotent stem cells (hiP...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607566/ https://www.ncbi.nlm.nih.gov/pubmed/23536886 http://dx.doi.org/10.1371/journal.pone.0059685 |
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author | Zeng, Liyun Zhang, Peilin Shi, Lingling Yamamoto, Vicky Lu, Wange Wang, Kai |
author_facet | Zeng, Liyun Zhang, Peilin Shi, Lingling Yamamoto, Vicky Lu, Wange Wang, Kai |
author_sort | Zeng, Liyun |
collection | PubMed |
description | Exonic deletions in NRXN1 have been associated with several neurodevelopmental disorders, including autism, schizophrenia and developmental delay. However, the molecular mechanism by which NRXN1 deletions impact neurodevelopment remains unclear. Here we used human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) as models to investigate the functional impacts of NRXN1 knockdown. We first generated hiPSCs from skin fibroblasts and differentiated them into neural stem cells (NSCs). We reduced NRXN1 expression in NSCs via a controlled shRNAmir-based knockdown system during differentiation, and monitored the transcriptome alteration by RNA-Seq and quantitative PCR at several time points. Interestingly, half reduction of NRXN1 expression resulted in changes of expression levels for the cell adhesion pathway (20 genes, P = 2.8×10(−6)) and neuron differentiation pathway (13 genes, P = 2.1×10(−4)), implicating that single-gene perturbation can impact biological networks important for neurodevelopment. Furthermore, astrocyte marker GFAP was significantly reduced in a time dependent manner that correlated with NRXN1 reduction. This observation was reproduced in both hiPSCs and hESCs. In summary, based on in vitro models, NRXN1 deletions impact several biological processes during neurodevelopment, including synaptic adhesion and neuron differentiation. Our study highlights the utility of stem cell models in understanding the functional roles of copy number variations (CNVs) in conferring susceptibility to neurodevelopmental diseases. |
format | Online Article Text |
id | pubmed-3607566 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36075662013-03-27 Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models Zeng, Liyun Zhang, Peilin Shi, Lingling Yamamoto, Vicky Lu, Wange Wang, Kai PLoS One Research Article Exonic deletions in NRXN1 have been associated with several neurodevelopmental disorders, including autism, schizophrenia and developmental delay. However, the molecular mechanism by which NRXN1 deletions impact neurodevelopment remains unclear. Here we used human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) as models to investigate the functional impacts of NRXN1 knockdown. We first generated hiPSCs from skin fibroblasts and differentiated them into neural stem cells (NSCs). We reduced NRXN1 expression in NSCs via a controlled shRNAmir-based knockdown system during differentiation, and monitored the transcriptome alteration by RNA-Seq and quantitative PCR at several time points. Interestingly, half reduction of NRXN1 expression resulted in changes of expression levels for the cell adhesion pathway (20 genes, P = 2.8×10(−6)) and neuron differentiation pathway (13 genes, P = 2.1×10(−4)), implicating that single-gene perturbation can impact biological networks important for neurodevelopment. Furthermore, astrocyte marker GFAP was significantly reduced in a time dependent manner that correlated with NRXN1 reduction. This observation was reproduced in both hiPSCs and hESCs. In summary, based on in vitro models, NRXN1 deletions impact several biological processes during neurodevelopment, including synaptic adhesion and neuron differentiation. Our study highlights the utility of stem cell models in understanding the functional roles of copy number variations (CNVs) in conferring susceptibility to neurodevelopmental diseases. Public Library of Science 2013-03-25 /pmc/articles/PMC3607566/ /pubmed/23536886 http://dx.doi.org/10.1371/journal.pone.0059685 Text en © 2013 Zeng et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Zeng, Liyun Zhang, Peilin Shi, Lingling Yamamoto, Vicky Lu, Wange Wang, Kai Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models |
title | Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models |
title_full | Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models |
title_fullStr | Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models |
title_full_unstemmed | Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models |
title_short | Functional Impacts of NRXN1 Knockdown on Neurodevelopment in Stem Cell Models |
title_sort | functional impacts of nrxn1 knockdown on neurodevelopment in stem cell models |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607566/ https://www.ncbi.nlm.nih.gov/pubmed/23536886 http://dx.doi.org/10.1371/journal.pone.0059685 |
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