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The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model

Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essent...

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Autores principales: Murai, Kiyohito, Sun, Guoqiang, Ye, Peng, Tian, E., Yang, Su, Cui, Qi, Sun, Guihua, Trinh, Daniel, Sun, Olivia, Hong, Teresa, Wen, Zhexing, Kalkum, Markus, Riggs, Arthur D., Song, Hongjun, Ming, Guo-li, Shi, Yanhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793043/
https://www.ncbi.nlm.nih.gov/pubmed/26965827
http://dx.doi.org/10.1038/ncomms10965
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author Murai, Kiyohito
Sun, Guoqiang
Ye, Peng
Tian, E.
Yang, Su
Cui, Qi
Sun, Guihua
Trinh, Daniel
Sun, Olivia
Hong, Teresa
Wen, Zhexing
Kalkum, Markus
Riggs, Arthur D.
Song, Hongjun
Ming, Guo-li
Shi, Yanhong
author_facet Murai, Kiyohito
Sun, Guoqiang
Ye, Peng
Tian, E.
Yang, Su
Cui, Qi
Sun, Guihua
Trinh, Daniel
Sun, Olivia
Hong, Teresa
Wen, Zhexing
Kalkum, Markus
Riggs, Arthur D.
Song, Hongjun
Ming, Guo-li
Shi, Yanhong
author_sort Murai, Kiyohito
collection PubMed
description Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essential regulator of NSC proliferation and self-renewal, inhibits miR-219 processing. miR-219 suppresses mouse NSC proliferation downstream of TLX. Moreover, we demonstrate upregulation of miR-219 and downregulation of TLX expression in NSCs derived from SCZ patient iPSCs and DISC1-mutant isogenic iPSCs. SCZ NSCs exhibit reduced cell proliferation. Overexpression of TLX or inhibition of miR-219 action rescues the proliferative defect in SCZ NSCs. Therefore, this study uncovers an important role for TLX and miR-219 in both normal neurodevelopment and in SCZ patient iPSC-derived NSCs. Moreover, this study reveals an unexpected role for TLX in regulating microRNA processing, independent of its well-characterized role in transcriptional regulation.
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spelling pubmed-47930432016-03-21 The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model Murai, Kiyohito Sun, Guoqiang Ye, Peng Tian, E. Yang, Su Cui, Qi Sun, Guihua Trinh, Daniel Sun, Olivia Hong, Teresa Wen, Zhexing Kalkum, Markus Riggs, Arthur D. Song, Hongjun Ming, Guo-li Shi, Yanhong Nat Commun Article Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essential regulator of NSC proliferation and self-renewal, inhibits miR-219 processing. miR-219 suppresses mouse NSC proliferation downstream of TLX. Moreover, we demonstrate upregulation of miR-219 and downregulation of TLX expression in NSCs derived from SCZ patient iPSCs and DISC1-mutant isogenic iPSCs. SCZ NSCs exhibit reduced cell proliferation. Overexpression of TLX or inhibition of miR-219 action rescues the proliferative defect in SCZ NSCs. Therefore, this study uncovers an important role for TLX and miR-219 in both normal neurodevelopment and in SCZ patient iPSC-derived NSCs. Moreover, this study reveals an unexpected role for TLX in regulating microRNA processing, independent of its well-characterized role in transcriptional regulation. Nature Publishing Group 2016-03-11 /pmc/articles/PMC4793043/ /pubmed/26965827 http://dx.doi.org/10.1038/ncomms10965 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 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/4.0/
spellingShingle Article
Murai, Kiyohito
Sun, Guoqiang
Ye, Peng
Tian, E.
Yang, Su
Cui, Qi
Sun, Guihua
Trinh, Daniel
Sun, Olivia
Hong, Teresa
Wen, Zhexing
Kalkum, Markus
Riggs, Arthur D.
Song, Hongjun
Ming, Guo-li
Shi, Yanhong
The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
title The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
title_full The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
title_fullStr The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
title_full_unstemmed The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
title_short The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model
title_sort tlx-mir-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia ipsc model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793043/
https://www.ncbi.nlm.nih.gov/pubmed/26965827
http://dx.doi.org/10.1038/ncomms10965
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