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TLX- miR-219 级联反应在神经发育和精神分裂症诱导多能干细胞模型中调节神经干细胞增殖。

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

作者信息

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

机构信息

Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.

Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.

出版信息

Nat Commun. 2016 Mar 11;7:10965. doi: 10.1038/ncomms10965.

DOI:10.1038/ncomms10965
PMID:26965827
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4793043/
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.

摘要

在精神分裂症（SCZ）等神经发育障碍中，已观察到脑特异性微小RNA miR - 219的表达失调。然而，其在正常哺乳动物神经干细胞（NSC）以及SCZ发病机制中的作用仍不清楚。我们在此表明，核受体TLX是NSC增殖和自我更新的关键调节因子，它会抑制miR - 219的加工过程。miR - 219在TLX下游抑制小鼠NSC的增殖。此外，我们证明了源自SCZ患者诱导多能干细胞（iPSC）和DISC1突变同基因iPSC的NSC中miR - 219上调且TLX表达下调。SCZ NSC表现出细胞增殖减少。过表达TLX或抑制miR - 219的作用可挽救SCZ NSC中的增殖缺陷。因此，本研究揭示了TLX和miR - 219在正常神经发育以及SCZ患者iPSC来源的NSC中的重要作用。此外，本研究揭示了TLX在调节微小RNA加工过程中的一个意外作用，这与其在转录调控中已明确的作用无关。

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