Nuclear Orphan Receptor TLX Induces Oct-3/4 for the Survival and Maintenance of Adult Hippocampal Progenitors upon Hypoxia
Nuclear Orphan Receptor TLX Induces Oct-3/4 for the Survival and Maintenance of Adult Hippocampal Progenitors upon Hypoxia
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DOI：
10.1074/jbc.m110.167445
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发表时间：
2011-03-18
影响因子：
4.8
通讯作者：
Funa, Keiko
中科院分区：
文献类型：
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作者：
Chavali, Pavithra Lakshminarasimhan;Saini, Ravi Kanth Rao;Funa, Keiko
低氧促进神经干细胞增殖，其机制尚不清楚。在这里，我们已经确定核孤儿受体TLX是缺氧时神经前体细胞增殖和多能性的媒介。我们发现在低氧条件下TLX的早期蛋白表达增强，增强了神经前体细胞的持续增殖。此外，在分化条件下，低氧诱导TLX会导致增殖和干细胞样表型，以及神经干细胞标记物的共同表达。低氧后，TLX被募集到Oct-3/4近端启动子，增强基因转录，促进祖细胞增殖和多能性。OCT-3/4基因的敲除显著降低了TLX介导的增殖，突显了它们在调节祖细胞池中的相互依赖。此外，TLX与碱性成纤维细胞生长因子协同作用，在缺氧时维持细胞活力，因为TLX被敲除并伴随着生长因子的退出导致细胞死亡。这可以归因于TLX激活Akt信号通路，该通路的耗尽导致祖细胞的增殖减少。总而言之，这里提供的数据显示了TLX在神经干细胞增殖和缺氧后的多能性中的新作用。
Hypoxia promotes neural stem cell proliferation, the mechanism of which is poorly understood. Here, we have identified the nuclear orphan receptor TLX as a mediator for proliferation and pluripotency of neural progenitors upon hypoxia. We found an enhanced early protein expression of TLX under hypoxia potentiating sustained proliferation of neural progenitors. Moreover, TLX induction upon hypoxia in differentiating conditions leads to proliferation and a stem cell-like phenotype, along with coexpression of neural stem cell markers. Following hypoxia, TLX is recruited to the Oct-3/4 proximal promoter, augmenting the gene transcription and promoting progenitor proliferation and pluripotency. Knockdown of Oct-3/4 significantly reduced TLX-mediated proliferation, highlighting their interdependence in regulating the progenitor pool. Additionally, TLX synergizes with basic FGF to sustain cell viability upon hypoxia, since the knockdown of TLX along with the withdrawal of growth factor results in cell death. This can be attributed to the activation of Akt signaling pathway by TLX, the depletion of which results in reduced proliferation of progenitor cells. Cumulatively, the data presented here demonstrate a new role for TLX in neural stem cell proliferation and pluripotency upon hypoxia.