title: Morphine modulates mouse hippocampal progenitor cell lineages by upregulating miR-181a level.
abstract: The mechanism by which addictive drugs such as morphine regulate adult neurogenesis remains elusive. We now demonstrate that morphine can regulate neurogenesis by control of miR-181a and subsequent hippocampal neural progenitor cell (hNPC) lineages. In the presence of morphine, hNPCs preferentially differentiated into astrocytes, an effect blocked by the specific μ-opioid receptor antagonist, Cys(2)-Tyr(3)-Orn(5)-Pen(7)-amide. This effect was mediated by the Prox1/Notch1 pathway as demonstrated by an increase in Notch1 level in the morphine- but not fentanyl-treated hNPCs and blocked by overexpression of Notch1 siRNA. Overexpression of Prox1 siRNA upregulated Notch1 level and potentiated the morphine-induced lineage changes. Prox1 transcript level was regulated by direct interaction between miR-181a and its 3'-UTR sequence. In vitro and in vivo treatment with morphine resulted in an increase in miR-181a level in hNPCs and mouse hippocampi, respectively. Overexpression of miR-181a mimics reduced Prox1 levels, increased Notch1 levels, and enhanced hNPCs differentiation into astrocytes. Meanwhile, overexpression of the miR-181a inhibitor raised Prox1 levels, decreased Notch1 levels, and subsequently blocked the morphine-induced lineage changes. Thus, by modulating Prox1/Notch1 activities via miR-181a, morphine influences the fate of differentiating hNPCs differentiation and therefore the ultimate quantities of mature neurons and astrocytes.
authors: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors: Chi
authors: C
authors: Xu
authors: Yue
authors: Y
authors: Zhang
authors: Hui
authors: H
authors: Zheng
authors: Horace H
authors: HH
authors: Loh
authors: Ping-Yee
authors: PY
authors: Law
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009020:Morphine / Q000494:pharmacology*; D058953:Neural Stem Cells / Q000166:cytology; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D025521:Tumor Suppressor Proteins; C529100:mirn181 microRNA, mouse; D000098551:Prospero-Related Homeobox 1 Protein; D009020:Morphine
keywords: Adult stem cells; Astrocytes; MicroRNA; Neural differentiation; Neural stem cell; Notch; Progenitor cells