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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 48 h after exposure to 10 nM 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 3 h after exposure to 10 nM MeHg, and cyclin E degradation 48 h 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 ofmore » cyclin E. - Highlights: • NPC proliferation was suppressed by 10 nM MeHg, but cell death was not observed. • MeHg induced down-regulation of cyclin E, a promoter of cell cycle progression. • GSK-3β was up-regulated by 10 nM MeHg, leading to cyclin E degradation. • GSK-3β inhibitors suppressed MeHg-induced degradation of cyclin E.« less

Authors:
 [1];  [2]
  1. Department of Basic Medical Science, National Institute for Minamata Disease, Kumamoto (Japan)
  2. Department of Clinical Medicine, National Institute for Minamata Disease, Kumamoto (Japan)
Publication Date:
OSTI Identifier:
22687762
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 288; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CALCIUM; CELL CYCLE; CELL PROLIFERATION; CEREBRAL CORTEX; CONCENTRATION RATIO; GLYCOGEN; INHIBITION; LABELLING; METHYLMERCURY; PHOSPHORYLATION; PHOSPHOTRANSFERASES; RATS; TETRAZOLIUM

Citation Formats

Fujimura, Masatake, E-mail: fujimura@nimd.go.jp, and Usuki, Fusako. 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. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2015.07.006.
Fujimura, Masatake, E-mail: fujimura@nimd.go.jp, & Usuki, Fusako. 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. United States. doi:10.1016/J.TAAP.2015.07.006.
Fujimura, Masatake, E-mail: fujimura@nimd.go.jp, and Usuki, Fusako. Thu . "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". United States. doi:10.1016/J.TAAP.2015.07.006.
@article{osti_22687762,
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},
author = {Fujimura, Masatake, E-mail: fujimura@nimd.go.jp and Usuki, Fusako},
abstractNote = {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 48 h after exposure to 10 nM 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 3 h after exposure to 10 nM MeHg, and cyclin E degradation 48 h 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. - Highlights: • NPC proliferation was suppressed by 10 nM MeHg, but cell death was not observed. • MeHg induced down-regulation of cyclin E, a promoter of cell cycle progression. • GSK-3β was up-regulated by 10 nM MeHg, leading to cyclin E degradation. • GSK-3β inhibitors suppressed MeHg-induced degradation of cyclin E.},
doi = {10.1016/J.TAAP.2015.07.006},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 288,
place = {United States},
year = {2015},
month = {10}
}