Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal.
Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal.
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DOI：
10.1038/ncb2001
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发表时间：
2010-01
影响因子：
21.3
通讯作者：
Shi, Yanhong
中科院分区：
文献类型：
--
作者：
Qu, Qiuhao;Sun, Guoqiang;Li, Wenwu;Yang, Su;Ye, Peng;Zhao, Chunnian;Yu, Ruth T;Gage, Fred H;Evans, Ronald M;Shi, Yanhong
核受体TLX（也称为NR 2 E1）是成体神经干细胞自我更新所必需的;然而，所涉及的分子机制仍然难以捉摸。在这里，我们表明TLX激活成年小鼠神经干细胞中的经典Wnt/β-catenin通路。此外，我们证明了Wnt/β-catenin信号传导在表皮生长因子和成纤维细胞生长因子存在下成体神经干细胞的增殖和自我更新中是重要的。Wnt 7a和活性β-catenin促进神经干细胞自我更新，而Wnt 7a的缺失或axin（一种β-catenin抑制剂）的慢病毒转导导致成体神经源性区域中细胞增殖减少。慢病毒转导活性β-连环蛋白导致成年脑室下区B型神经干细胞数量增加，而Wnt 7 a或TLX缺失导致成年脑中保留溴脱氧尿苷标记的神经干细胞数量减少。Wnt 7a和活性β-连环蛋白都显著地挽救了TLX（也称为Nr 2 e1）短干扰RNA诱导的神经干细胞增殖缺陷。活性β-连环蛋白的慢病毒转导显著增加了TLR缺失的成年脑的神经源性区域中的细胞增殖。这些结果有力地支持了TLX通过Wnt/β-catenin途径调节神经干细胞增殖和自我更新的假设。此外，这项研究表明，神经干细胞可以通过分泌以自分泌/旁分泌模式起作用的信号分子来促进自身的自我更新。
The nuclear receptor TLX (also known as NR2E1) is essential for adult neural stem cell self-renewal; however, the molecular mechanisms involved remain elusive. Here we show that TLX activates the canonical Wnt/β-catenin pathway in adult mouse neural stem cells. Furthermore, we demonstrate that Wnt/β-catenin signalling is important in the proliferation and self-renewal of adult neural stem cells in the presence of epidermal growth factor and fibroblast growth factor. Wnt7a and active β-catenin promote neural stem cell self-renewal, whereas the deletion of Wnt7a or the lentiviral transduction of axin, a β-catenin inhibitor, led to decreased cell proliferation in adult neurogenic areas. Lentiviral transduction of active β-catenin led to increased numbers of type B neural stem cells in the subventricular zone of adult brains, whereas deletion of Wnt7a or TLX resulted in decreased numbers of neural stem cells retaining bromodeoxyuridine label in the adult brain. Both Wnt7a and active β-catenin significantly rescued a TLX (also known as Nr2e1) short interfering RNA-induced deficiency in neural stem cell proliferation. Lentiviral transduction of an active β-catenin increased cell proliferation in neurogenic areas of TLX-null adult brains markedly. These results strongly support the hypothesis that TLX acts through the Wnt/β-catenin pathway to regulate neural stem cell proliferation and self-renewal. Moreover, this study suggests that neural stem cells can promote their own self-renewal by secreting signalling molecules that act in an autocrine/paracrine mode.