Expression and function of orphan nuclear receptor TLX in adult neural stem cells
Expression and function of orphan nuclear receptor TLX in adult neural stem cells
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DOI：
10.1038/nature02211
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发表时间：
2004-01-01
期刊：
影响因子：
64.8
通讯作者：
Evans, RM
中科院分区：
文献类型：
--
作者：
Shi, YH;Lie, DC;Evans, RM
成人大脑中神经发生的发现导致了成人神经干细胞的发现(1)。TLX最初被鉴定为一种在脊椎动物前脑中表达的孤儿核受体(2)，在成年脑中高度表达(3)。据报道，TLX基因缺失小鼠的大脑在胚胎发育过程中没有明显的缺陷(4)；然而，成熟小鼠患有视网膜病变(5)、严重的边缘缺陷、攻击性、交配减少和逐渐的暴力行为(4，6)。在这里，我们显示TLX维持成人神经干细胞处于未分化的、增殖的状态。我们发现，通过荧光激活细胞分选(FACS)从成人脑中分离出的表达TLX的细胞可以在体外增殖、自我更新和分化为所有类型的神经细胞。相比之下，从成年突变脑组织中分离的TLX缺失细胞无法增殖。将TLX重新引入FACS分选的TLX阴性细胞，挽救了它们的增殖和自我更新能力。在体内，TLX突变小鼠表现出细胞增殖丧失，成年大脑神经源性区域巢蛋白标记减少。TLX可以沉默神经干细胞中星形胶质细胞标记物GFAP的胶质细胞特异性表达，表明转录抑制可能在维持这些细胞的未分化状态中起关键作用。
The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells(1). TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains(2) and is highly expressed in the adult brain(3). The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis(4); however, mature mice suffer from retinopathies(5), severe limbic defects, aggressiveness, reduced copulation and progressively violent behaviour(4,6). Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labelling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells.