title: Low concentrations of methylmercury inhibit neural progenitor cell proliferation associated with up-regulation of glycogen synthase kinase 3β and subsequent degradation of cyclin E in rats.
abstract: Methylmercury (MeHg) is an environmental neurotoxicant. The developing nervous system is susceptible to low concentrations of MeHg; however, the effect of MeHg on neural progenitor cell (NPC) proliferation, a key stage of neurogenesis during development, remains to be clarified. In this study, we investigated the effect of low concentrations of MeHg on NPCs by using a primary culture system developed using the embryonic rat cerebral cortex. NPC proliferation was suppressed 48h after exposure to 10nM MeHg, but cell death was not observed. Western blot analyses for cyclins A, B, D1, and E demonstrated that MeHg down-regulated cyclin E, a promoter of the G1/S cell cycle transition. Cyclin E has been shown to be degraded following the phosphorylation by glycogen synthase kinase 3β (GSK-3β). The time course study showed that GSK-3β was up-regulated 3h after exposure to 10nM MeHg, and cyclin E degradation 48h after MeHg exposure. We further demonstrated that GSK-3β inhibitors, lithium and SB-415286, suppressed MeHg-induced inhibition of NPC proliferation by preventing cyclin E degradation. These results suggest that the inhibition of NPC proliferation induced by low concentration of MeHg was associated with up-regulation of GSK-3β at the early stage and subsequent degeneration of cyclin E.
authors.affiliation: Department of Basic Medical Science, National Institute for Minamata Disease, Kumamoto, Japan. Electronic address: fujimura@nimd.go.jp.
authors.forename: Masatake
authors.initials: M
authors.lastname: Fujimura
authors.affiliation: Department of Clinical Medicine, National Institute for Minamata Disease, Kumamoto, Japan.
authors.forename: Fusako
authors.initials: F
authors.lastname: Usuki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019927:Cyclin E / Q000378:metabolism*; D004785:Environmental Pollutants / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008767:Methylmercury Compounds / Q000633:toxicity*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D019927:Cyclin E; D004785:Environmental Pollutants; D008767:Methylmercury Compounds; D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C004925:methylmercuric chloride
keywords: Cyclin E; Degradation; Glycogen synthase kinase 3β; Methylmercury; Neural progenitor cell; Proliferation