title: Morphine Promotes Astrocyte-Preferential Differentiation of Mouse Hippocampal Progenitor Cells via PKCε-Dependent ERK Activation and TRBP Phosphorylation.
abstract: Previously we have shown that morphine regulates adult neurogenesis by modulating miR-181a maturation and subsequent hippocampal neural progenitor cell (NPC) lineages. Using NPCs cultured from PKCε or β-arrestin2 knockout mice and the MAPK/ERK kinase 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 TAR RNA-binding protein (TRBP), a cofactor of Dicer. This augments Dicer activity and promotes the maturation of miR-181a. Furthermore, 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.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Xu
authors.affiliation: Stem Cell and Cancer Biology Group, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D009020:Morphine; D051744:Protein Kinase C-epsilon; D016601:RNA-Binding Proteins; D000099253:Trans-Activation Responsive RNA-Binding Protein
keywords: Adult stem cells; Cell signaling; MAPK; Neural differentiation; Neural stem cell; Progenitor cells; Signal transduction; miRNA