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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Nature Publishing Group
2016
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793043/ |
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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 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/ |
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Open Access Journal |
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Foreign Institution |
| institution |
US National Center for Biotechnology Information |
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NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| 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 |
| spellingShingle |
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 |
| 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 |
| title |
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_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_sort |
tlx-mir-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia ipsc model |
| 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. |
| publisher |
Nature Publishing Group |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793043/ |
| _version_ |
1613552298701619200 |