ASK1 inhibits astroglial development via p38 mitogen-activated protein kinase and promotes neuronal differentiation in adult hippocampus-derived progenitor cells
ASK1 inhibits astroglial development via p38 mitogen-activated protein kinase and promotes neuronal differentiation in adult hippocampus-derived progenitor cells
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DOI：
10.1128/mcb.24.1.280-293.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Funa, K
中科院分区：
文献类型：
--
作者：
Faigle, R;Brederlau, A;Funa, K
神经干细胞的分化和谱系特化的调控机制仍知之甚少，参与这一过程的许多分子及其特异性功能尚不清楚。我们研究了细胞凋亡信号调节激酶1（ASK1）对神经干细胞的影响，通过感染成年大鼠海马来源的祖细胞与腺病毒编码的组成型活性形式的ASK1。在ASK 1过表达后，观察到大量细胞分化为神经元，并且Mash1转录显著增加。此外，观察到神经胶质细胞的显著消耗，即使在用有效的神经胶质诱导剂如白血病抑制因子和骨形态发生蛋白对ASK 1感染的培养物进行额外处理后也持续存在。对胶质细胞酸性蛋白启动子的分析表明，ASK1是胶质细胞特异性基因转录的有效抑制剂。然而，信号转导和转录激活因子3（STAT3）的结合位点的启动子是无效的，而p38丝裂原活化蛋白激酶的激活是至关重要的，这表明存在一个新的机制，抑制胶质细胞分化。
The mechanisms controlling differentiation and lineage specification of neural stem cells are still poorly understood, and many of the molecules involved in this process and their specific functions are yet unknown. We investigated the effect of apoptosis signal-regulating kinase 1 (ASK1) on neural stem cells by infecting adult hippocampus-derived rat progenitors with an adenovirus encoding the constitutively active form of ASK1. Following ASK1 overexpression, a significantly larger number of cells differentiated into neurons and a substantial increase in Mash1 transcription was observed. Moreover, a marked depletion of glial cells was observed, persisting even after additional treatment of ASK1-infected cultures with potent glia inducers such as leukemia inhibitory factor and bone morphogenetic protein. Analysis of the promoter for glial fibrillary acidic protein revealed that ASK1 acts as a potent inhibitor of glial-specific gene transcription. However, the signal transducers and activators of transcription 3 (STAT3)-binding site in the promoter was dispensable, while the activation of p38 mitogen-activated protein kinase was crucial for this effect, suggesting the presence of a novel mechanism for the inhibition of glial differentiation.