TLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitors
TLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitors
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DOI：
10.1016/j.mcn.2010.06.003
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发表时间：
2010-10-01
影响因子：
3.5
通讯作者：
Funa, Keiko
中科院分区：
文献类型：
--
作者：
Elmi, Muna;Matsumoto, Yoshiki;Funa, Keiko
孤儿核受体TLX已被提出作为细胞周期抑制剂的阻遏物，以维持神经干细胞处于未分化状态，并防止定型为星形胶质细胞谱系。然而，关于TLX在神经元谱系定型和分化中的作用机制知之甚少。在FGF存在下培养的大多数成年大鼠海马衍生的祖细胞（AHP）表达高水平的TLX，并且这些细胞的一部分还表达原神经基因MASH 1。在FGF撤除后，TLX迅速降低，而MASH 1在1 h内强烈表达，逐渐降低至24 h消失。在不存在FGF的情况下，TLX在AHP细胞中的腺病毒转导瞬时增加细胞增殖，然而，随后通过诱导MASH 1、神经生成素1、DCX和MAP 2ab导致神经元分化。此外，TLX通过与Sp1相互作用直接靶向并激活MASH 1启动子，募集共激活因子，而消除共阻遏因子HDAC 4。相反，在AHPs中TLX的沉默降低β-III微管蛋白和DCX的表达，并促进胶质细胞分化。因此，我们的研究结果表明，TLX不仅作为细胞周期和胶质细胞分化的阻遏物，但也激活神经元谱系承诺在AHPs。(C)2010年爱思唯尔公司All rights reserved.
The orphan nuclear receptor TLX has been proposed to act as a repressor of cell cycle inhibitors to maintain the neural stem cells in an undifferentiated state, and prevents commitment into astrocyte lineages. However, little is known about the mechanism of TLX in neuronal lineage commitment and differentiation. A majority of adult rat hippocampus-derived progenitors (AHPs) cultured in the presence of FGF express a high level of TLX and a fraction of these cells also express the proneural gene MASH1. Upon FGF withdrawal, TLX rapidly decreased, while MASH1 was intensely expressed within 1 h, decreasing gradually to disappear at 24 h. Adenoviral transduction of TLX in AHP cells in the absence of FGF transiently increased cell proliferation, however, later resulted in neuronal differentiation by inducing MASH1, Neurogenin1, DCX, and MAP2ab. Furthermore, TLX directly targets and activates the MASH1 promoter through interaction with Sp1, recruiting co-activators whereas dismissing the co-repressor HDAC4. Conversely, silencing of TLX in AHPs decreased beta-III tubulin and DCX expression and promoted glial differentiation. Our results thus suggest that TLX not only acts as a repressor of cell cycle and glial differentiation but also activates neuronal lineage commitment in AHPs. (C) 2010 Elsevier Inc. All rights reserved.