The effects of methylmercury on Notch signaling during embryonic neural development in Drosophila melanogaster.
Methylmercury (MeHg) is a ubiquitous toxicant that targets the developing fetal nervous system. MeHg interacts with the Notch signaling pathway, a highly-conserved intercellular signaling mechanism required for normal development. Notch signaling is conveyed by activation of the genes in the enhancer of split (E(spl)) locus in Drosophila. We have previously shown that acute high doses of MeHg upregulate several E(spl) genes in Drosophila neural-derived C6 cells. Furthermore, MeHg induction of E(spl) can occur independent of the Notch receptor itself. We now show that MeHg, unlike inorganic mercury (HgCl2), preferentially upregulates E(spl)mδ and E(spl)mγ in Drosophila C6 cells. This is distinct from Delta ligand-induced Notch signaling in which no induction of E(spl)mδ is seen. MeHg is also seen to specifically upregulate E(spl)mδ in Drosophila embryos where HgCl2 showed no such effect. Additionally, treatment of embryos with MeHg caused a consistent failure in axonal outgrowth of the intersegmental nerve (ISN). This ISN phenotype was partially replicated by genetic activation of the Notch pathway, but was not replicated by increasing expression of E(spl)mδ. These data suggest a role for Notch signaling and the E(spl)mδ target gene in MeHg toxicity, however, the site of action for E(spl)mδ in this system remains to be elucidated.
Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, USA.
G L
GL
Engel
A
A
Delwig
M D
MD
Rand
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008767:Methylmercury Compounds / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*
D051792:Basic Helix-Loop-Helix Proteins; D029721:Drosophila Proteins; D008767:Methylmercury Compounds; D051880:Receptors, Notch; D012097:Repressor Proteins; C084530:E(spl)mdelta-HLH protein, Drosophila; C077964:E(spl)mgamma-HLH protein, Drosophila; C004925:methylmercuric chloride