Morphine Promotes Astrocyte-Preferential Differentiation of Mouse Hippocampal Progenitor Cells via PKCε-Dependent ERK Activation and TRBP Phosphorylation.
Morphine Promotes Astrocyte-Preferential Differentiation of Mouse Hippocampal Progenitor Cells via PKCε-Dependent ERK Activation and TRBP Phosphorylation.
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DOI：
10.1002/stem.2055
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Law PY
中科院分区：
文献类型：
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作者：
Xu C;Zheng H;Loh HH;Law PY
以前，我们已经表明，吗啡通过调节miR-181 a成熟和随后的海马神经祖细胞（NPC）谱系来调节成体神经发生。通过使用从PKCε或β-arrestin 2敲除小鼠培养的NPC和MEK抑制剂U 0126，我们证明了通过miR-181 a/Prox 1/Notch 1途径调节NPC分化具有配体依赖性选择性。在NPC中，吗啡和芬太尼分别通过PKCε-和β-arrestin依赖性途径激活ERK。芬太尼暴露后，激活的磷酸化ERK易位到细胞核。相反，在吗啡处理后，磷酸化ERK保留在胞质溶胶中，并能够磷酸化TRBP，Dicer的辅因子。这增强了Dicer活性并促进了miR-181 a的成熟。此外，通过使用转染野生型TRBP、SΔA和SΔD TRBP突变体的NPC，我们证实了TRBP磷酸化在Dicer活性、miR-181 a成熟以及最终吗啡诱导的NPC星形胶质细胞优先分化中的关键作用。因此，吗啡通过PKCε依赖性ERK激活以及随后的TRBP磷酸化和miR-181 a成熟来调节NPC的谱系特异性分化。
Previously we have shown that morphine regulates adult neurogenesis by modulating miR-181a maturation and subsequent hippocampal neural progenitor cell (NPC) lineages. By using NPCs cultured from PKCε or β-arrestin2 knockout mice and the MEK inhibitor U0126, we demonstrate that regulation of NPC differentiation via the miR-181a/Prox1/Notch1 pathway exhibits ligand-dependent selectivity. In NPCs, morphine and fentanyl activate ERK via the PKCε- and β-arrestin-dependent pathways, respectively. After fentanyl exposure, the activated phospho-ERK translocates to the nucleus. Conversely, after morphine treatment phospho-ERK remains in the cytosol and is capable of phosphorylating TRBP, a cofactor of Dicer. This augments Dicer activity and promotes the maturation of miR-181a. Furthermore, by using NPCs transfected with wild type TRBP, SΔA and SΔD TRBP mutants, we confirmed the crucial role of TRBP phosphorylation in Dicer activity, miR-181a maturation, and finally the morphine-induced astrocyte-preferential differentiation of NPCs. Thus, morphine modulates the lineage-specific differentiation of NPCs by PKCε-dependent ERK activation with subsequent TRBP phosphorylation and miR-181a maturation.