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

Author

Listed:
  • Kiyohito Murai

    (Cancer Center, Beckman Research Institute of City of Hope)

  • Guoqiang Sun

    (Cancer Center, Beckman Research Institute of City of Hope)

  • Peng Ye

    (Cancer Center, Beckman Research Institute of City of Hope)

  • E. Tian

    (Cancer Center, Beckman Research Institute of City of Hope)

  • Su Yang

    (Cancer Center, Beckman Research Institute of City of Hope
    Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope)

  • Qi Cui

    (Cancer Center, Beckman Research Institute of City of Hope
    Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope)

  • Guihua Sun

    (Beckman Research Institute of City of Hope)

  • Daniel Trinh

    (Cancer Center, Beckman Research Institute of City of Hope)

  • Olivia Sun

    (Cancer Center, Beckman Research Institute of City of Hope)

  • Teresa Hong

    (Beckman Research Institute of City of Hope)

  • Zhexing Wen

    (Institute for Cell Engineering, Johns Hopkins University School of Medicine)

  • Markus Kalkum

    (Beckman Research Institute of City of Hope)

  • Arthur D. Riggs

    (Beckman Research Institute of City of Hope)

  • Hongjun Song

    (Institute for Cell Engineering, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Guo-li Ming

    (Institute for Cell Engineering, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Yanhong Shi

    (Cancer Center, Beckman Research Institute of City of Hope
    Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope)

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.

Suggested Citation

  • 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, 2016. "The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10965
    DOI: 10.1038/ncomms10965
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