The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model.
The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model.
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DOI：
10.1038/ncomms10965
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发表时间：
2016-03-11
影响因子：
16.6
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Murai K;Sun G;Ye P;Tian E;Yang S;Cui Q;Sun G;Trinh D;Sun O;Hong T;Wen Z;Kalkum M;Riggs AD;Song H;Ming GL;Shi Y
在神经发育障碍如精神分裂症（SCZ）中观察到miR-219（一种脑特异性microRNA）表达失调。然而，其在正常哺乳动物神经干细胞（NSCs）和SCZ发病机制中的作用仍然未知。我们在这里表明，核受体TLX，NSC增殖和自我更新的重要调节剂，抑制miR-219加工。miR-219抑制TLX下游的小鼠NSC增殖。此外，我们证明了在源自SCZ患者iPSC和DISC 1突变体等基因iPSC的NSC中miR-219的上调和TLX表达的下调。SCZ NSC表现出降低的细胞增殖。TLX的过表达或miR-219作用的抑制挽救了SCZ NSC中的增殖缺陷。因此，本研究揭示了TLX和miR-219在正常神经发育和SCZ患者iPSC衍生的NSC中的重要作用。此外，这项研究揭示了TLX在调节microRNA加工中的意想不到的作用，独立于其在转录调节中的良好特征。 microRNA的失调与神经发育障碍有关，包括精神分裂症。在这里，作者表明TLX-miR-219级联调节正常发育期间神经干细胞的增殖，并且该途径在精神分裂症iPSC模型中失调。
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. Dysregulation of microRNAs has been implicated in neurodevelopmental disorders, including schizophrenia. Here the authors show that the TLX-miR-219 cascade regulates the proliferation of neural stem cells during normal development, and this pathway is dysregulated in a schizophrenia iPSC model.