Activation of postnatal neural stem cells requires nuclear receptor TLX.
Activation of postnatal neural stem cells requires nuclear receptor TLX.
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DOI：
10.1523/jneurosci.1038-11.2011
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发表时间：
2011-09-28
期刊：
影响因子：
--
通讯作者：
Zhang CL
中科院分区：
文献类型：
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作者：
Niu W;Zou Y;Shen C;Zhang CL
神经干细胞(NSCs)在出生后的大脑中不断产生新的神经元。然而，这些细胞中的大多数保持在不分裂、不活跃的状态。这些细胞进入增殖所需的分子机制在很大程度上仍不清楚。在这里，我们发现核受体TLX(NR2E1)控制着小鼠出生后神经干细胞的激活状态。谱系追踪表明，表达TLX的细胞可以引起出生后激活和不活跃的神经干细胞。令人惊讶的是，TLX功能的丧失并不会导致神经胶质细胞的自发分化，而是会导致NSCs标记表达和放射状形态的非活跃细胞随年龄的急剧增加。这些不活跃的细胞在发育过程中错位分布在齿状回的颗粒细胞层中，在重新引入异位TLX后可以再次增殖。对分选的NSCs的RNA-seq分析显示了TLX依赖的全球表达特征，其中包括P53信号通路。TLX以P53依赖的方式调节p21的表达，急性去除P53可以挽救培养中TLX缺失的神经干细胞的增殖缺陷。综上所述，这些发现表明TLX作为一个重要的调节因子，通过与P53和其他信号通路的遗传相互作用来控制出生后NSCs的激活，从而确保出生后NSCs的增殖能力。
Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a non-dividing, inactive state. The molecular mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphology for NSCs. These inactive cells are mis-positioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroducing ectopic TLX. RNA-seq analysis of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulates p21 expression in a p53-dependent manner and acute removal of p53 can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.