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

Kiyohito Murai; Guoqiang Sun; Peng Ye; E. Tian; Su Yang; Qi Cui; Guihua Sun; Daniel Trinh; Olivia Sun; Teresa Hong; Zhexing Wen; Markus Kalkum; Arthur D. Riggs; Hongjun Song; Guo Li Ming; Yanhong Shi

doi:10.1038/ncomms10965

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

Kiyohito Murai, Guoqiang Sun, Peng Ye, E. Tian, Su Yang, Qi Cui, Guihua Sun, Daniel Trinh, Olivia Sun, Teresa Hong, Zhexing Wen, Markus Kalkum, Arthur D. Riggs, Hongjun Song, Guo Li Ming, Yanhong Shi

School of Medicine

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

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.

Original language	English (US)
Article number	10965
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10965
State	Published - Mar 11 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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@article{2e877595666143b1b851cd378e6aa809,

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

abstract = "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.",

author = "Kiyohito Murai and Guoqiang Sun and Peng Ye and E. Tian and Su Yang and Qi Cui and Guihua Sun and Daniel Trinh and Olivia Sun and Teresa Hong and Zhexing Wen and Markus Kalkum and Riggs, {Arthur D.} and Hongjun Song and Ming, {Guo Li} and Yanhong Shi",

note = "Funding Information: We thank Dr VN Kim for providing the pCK-Flag-Drosha and pCK-Flag-DGCR8 plasmids. This work was supported by Sidell Kagan Foundation and California Institute for Regenerative Medicine TR2-01832 and RB4-06277 to Y.S., and NIH (NS048271, MH105128), NARSAD and MSCRF to G-l.M. D.T. is a Bridge student supported by the California Institute for Regenerative Medicine Bridges to Stem Cell Research Award to California State University Long Beach (TB1-01182). Research reported in this publication included work performed in Integrative Genomics and Drug Discovery and Structural Biology Cores supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.",

year = "2016",

month = mar,

day = "11",

doi = "10.1038/ncomms10965",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model

AU - Murai, Kiyohito

AU - Sun, Guoqiang

AU - Ye, Peng

AU - Tian, E.

AU - Yang, Su

AU - Cui, Qi

AU - Sun, Guihua

AU - Trinh, Daniel

AU - Sun, Olivia

AU - Hong, Teresa

AU - Wen, Zhexing

AU - Kalkum, Markus

AU - Riggs, Arthur D.

AU - Song, Hongjun

AU - Ming, Guo Li

AU - Shi, Yanhong

N1 - Funding Information: We thank Dr VN Kim for providing the pCK-Flag-Drosha and pCK-Flag-DGCR8 plasmids. This work was supported by Sidell Kagan Foundation and California Institute for Regenerative Medicine TR2-01832 and RB4-06277 to Y.S., and NIH (NS048271, MH105128), NARSAD and MSCRF to G-l.M. D.T. is a Bridge student supported by the California Institute for Regenerative Medicine Bridges to Stem Cell Research Award to California State University Long Beach (TB1-01182). Research reported in this publication included work performed in Integrative Genomics and Drug Discovery and Structural Biology Cores supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

PY - 2016/3/11

Y1 - 2016/3/11

N2 - 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.

AB - 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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U2 - 10.1038/ncomms10965

DO - 10.1038/ncomms10965

M3 - Article

C2 - 26965827

AN - SCOPUS:84961709637

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 10965

ER -

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

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