Methylmercury inhibits differentiation of rat neural stem cells via Notch signalling.
The Notch receptor is essential for neural stem cell (NSC) characteristics. Relatively high concentrations (micromolar) of methylmercury (MeHg) activate Notch signalling in Drosophila cell lines; however, exposure of MeHg at such concentrations is rare, and the implications for mammalian cells are unclear. We have shown that MeHg at a nanomolar range inhibits neuronal differentiation of rodent embryonic NSCs. Here we show that low MeHg levels (2.5-10 nM) activated Notch signalling in NSCs, as assessed by the increased activity in a specific Notch-reporter assay and by the increased cleavage of the Notch intracellular domain. Importantly, pretreatment with Notch cleavage inhibitor reversed the MeHg-induced repression of neuronal differentiation, suggesting that Notch activation is involved in the inhibition of NSC differentiation by environmentally relevant levels of MeHg.
Tamm
Christoffer
C
Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
Duckworth
Joshua K
JK
Hermanson
Ola
O
Ceccatelli
Sandra
S
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D008345:Manganese / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D008767:Methylmercury Compounds / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects*; D013687:Telencephalon / Q000166:cytology; D014162:Transfection
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; D008767:Methylmercury Compounds; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D051880:Receptors, Notch; D008345:Manganese