Differential effects of MEK inhibitors on rat neural stem cell differentiation: Repressive roles of MEK2 in neurogenesis and induction of astrocytogenesis by PD98059
Differential effects of MEK inhibitors on rat neural stem cell differentiation: Repressive roles of MEK2 in neurogenesis and induction of astrocytogenesis by PD98059
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DOI：
10.1016/j.phrs.2019.104466
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发表时间：
2019-11-01
影响因子：
9.3
通讯作者：
Kim, Hyun-Jung
中科院分区：
文献类型：
--
作者：
Lee, Ha-Rim;Lee, Jeewoo;Kim, Hyun-Jung
神经干细胞（NSCs）在不同的培养环境下增殖并分化为神经元和胶质细胞。然而，决定NSCs命运的潜在机制尚不完全清楚。生长因子通过丝裂原激活蛋白激酶(MAPK)/细胞外信号调节激酶（ERIC）激酶（MEK）和MAPK激活促进NSC增殖，当从培养基中提取丝裂原时，NSCs分化为神经元、星形胶质细胞或少突胶质细胞。在这里，我们旨在确定MEK信号在决定NSC命运中的作用和作用。MEK抑制剂U0126、SL327和PD98059对NSC分化有不同的影响。U0126和SL327，已知能抑制MEK1和MEK2，诱导神经元分化，而PD98059，在较高浓度下优先抑制MEK1，增加星形细胞发生。使用小干扰RNA敲低MEK2可增加神经发生，而过表达野生型（WT） MEK2可抑制神经发生，提示MEK2在神经元分化中的抑制作用。PD98059的化学结构对诱导星形细胞发生很重要，因为不仅PD98059（2′-氨基-3′-甲氧基黄酮）及其化学结构类似物3′-甲氧基黄酮促进了星形细胞发生。因此，在我们的研究中，我们认为MEK抑制剂在决定NSC命运方面具有不同的功能。抑制MEK2对于诱导NSCs的神经发生是重要的。U0126和SL327通过抑制MEK2增加神经发生，而PD98059诱导NSCs的星形细胞发生，这是由化学结构介导的，特别是3'-甲氧基，而不是其著名的MEK1抑制。
Neural stern cells (NSCs) proliferate and differentiate into neurons and glia depending on the culture environment. However, the underlying mechanisms determining the fate of NSCs are not fully understood. Growth factors facilitate NSC proliferation through mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERIC) kinase (MEK) and MAPK activation, and NSCs differentiate into neurons, astrocytes, or oligodendrocytes when mitogens are withdrawn from the culture media. Here, we aimed to identify the effects and roles of MEK signaling on the determination of NSC fate. MEK inhibitors, U0126, SL327, and PD98059, had differential effects on NSC differentiation. U0126 and SL327, which are known to inhibit MEK1 and MEK2, induced neuronal differentiation, whereas PD98059, which is reported to preferentially inhibit MEK1 at higher concentrations, increased astrocytogenesis. Knockdown of MEK2 using small interfering RNA increased neurogenesis and over-expression of wild type (WT) MEK2 inhibited neurogenesis, suggesting a repressive role of MEK2 in neuronal differentiation. The chemical structure of PD98059 appears to be important for induction of astrocytogenesis because not only PD98059 (2'-amino-3'-methoxyflavone) but also its chemical structural mimetic, 3'-methoxyflavone, enhanced astrocytogenesis. Therefore, in our study, we suggest that MEK inhibitors have distinct functions in determining NSC fate. Inhibition of MEK2 is important for induction of neurogenesis in NSCs. U0126 and SL327 increase neurogenesis through MEK2 inhibition, whereas PD98059 induced astrocytogenesis in NSCs, which is mediated by the chemical structure, particularly the 3'-methoxy group rather than its renowned MEK1 inhibition.