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Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells
The canonical Wnt signal pathway plays a pivotal role in anteroposterior patterning and midbrain specification during early neurogenesis. Activating Wnt signal has been a strategy for differentiating human pluripotent stem cells (PSCs) into midbrain dopaminergic (DA) neurons; however, the underlying...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938028/ https://www.ncbi.nlm.nih.gov/pubmed/29650976 http://dx.doi.org/10.1038/s12276-018-0044-y |
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author | Kim, Ji Young Lee, Jae Souk Hwang, Hyun Sub Lee, Dongjin R. Park, Chul-Yong Jung, Sung Jun You, Young Rang Kim, Dae-Sung Kim, Dong-Wook |
author_facet | Kim, Ji Young Lee, Jae Souk Hwang, Hyun Sub Lee, Dongjin R. Park, Chul-Yong Jung, Sung Jun You, Young Rang Kim, Dae-Sung Kim, Dong-Wook |
author_sort | Kim, Ji Young |
collection | PubMed |
description | The canonical Wnt signal pathway plays a pivotal role in anteroposterior patterning and midbrain specification during early neurogenesis. Activating Wnt signal has been a strategy for differentiating human pluripotent stem cells (PSCs) into midbrain dopaminergic (DA) neurons; however, the underlying molecular mechanism(s) of how the Wnt signal drives posterior fate remained unclear. In this study, we found that activating the canonical Wnt signal significantly upregulated the expression of EN1, a midbrain-specific marker, in a fibroblast growth factor signal-dependent manner in human PSC-derived neural precursor cells (NPCs). The EN1 promoter region contains a putative TCF4-binding site that directly interacts with the β-catenin/TCF complex upon Wnt signal activation. Once differentiated, NPCs treated with a Wnt signal agonist gave rise to functional midbrain neurons including glutamatergic, GABAergic, and DA neurons. Our results provide a potential molecular mechanism that underlies midbrain specification of human PSC-derived NPCs by Wnt activation, as well as a differentiation paradigm for generating human midbrain neurons that may serve as a cellular platform for studying the ontogenesis of midbrain neurons and neurological diseases relevant to the midbrain. |
format | Online Article Text |
id | pubmed-5938028 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59380282018-05-15 Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells Kim, Ji Young Lee, Jae Souk Hwang, Hyun Sub Lee, Dongjin R. Park, Chul-Yong Jung, Sung Jun You, Young Rang Kim, Dae-Sung Kim, Dong-Wook Exp Mol Med Article The canonical Wnt signal pathway plays a pivotal role in anteroposterior patterning and midbrain specification during early neurogenesis. Activating Wnt signal has been a strategy for differentiating human pluripotent stem cells (PSCs) into midbrain dopaminergic (DA) neurons; however, the underlying molecular mechanism(s) of how the Wnt signal drives posterior fate remained unclear. In this study, we found that activating the canonical Wnt signal significantly upregulated the expression of EN1, a midbrain-specific marker, in a fibroblast growth factor signal-dependent manner in human PSC-derived neural precursor cells (NPCs). The EN1 promoter region contains a putative TCF4-binding site that directly interacts with the β-catenin/TCF complex upon Wnt signal activation. Once differentiated, NPCs treated with a Wnt signal agonist gave rise to functional midbrain neurons including glutamatergic, GABAergic, and DA neurons. Our results provide a potential molecular mechanism that underlies midbrain specification of human PSC-derived NPCs by Wnt activation, as well as a differentiation paradigm for generating human midbrain neurons that may serve as a cellular platform for studying the ontogenesis of midbrain neurons and neurological diseases relevant to the midbrain. Nature Publishing Group UK 2018-04-13 /pmc/articles/PMC5938028/ /pubmed/29650976 http://dx.doi.org/10.1038/s12276-018-0044-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which permits any non-commercial 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 license, and indicate if changes were made. If you remix, transform, or build upon this article or a part thereof, you must distribute your contributions under the same license as the original. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/. |
spellingShingle | Article Kim, Ji Young Lee, Jae Souk Hwang, Hyun Sub Lee, Dongjin R. Park, Chul-Yong Jung, Sung Jun You, Young Rang Kim, Dae-Sung Kim, Dong-Wook Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells |
title | Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells |
title_full | Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells |
title_fullStr | Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells |
title_full_unstemmed | Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells |
title_short | Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells |
title_sort | wnt signal activation induces midbrain specification through direct binding of the beta-catenin/tcf4 complex to the en1 promoter in human pluripotent stem cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938028/ https://www.ncbi.nlm.nih.gov/pubmed/29650976 http://dx.doi.org/10.1038/s12276-018-0044-y |
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