Mechanisms of Methylmercury Toxicity in Notch signaling and Neuromuscular Development
The developing nervous system has long been understood to be a MeHg target. We have engaged in several unbiased genetic screen approaches using the Drosophila (fruitfly) model to identify novel candidate genes and pathways that function in development and moderate MeHg toxicity. Using a transcriptomic approach in fly embryos we first identified a MeHg induced expression of Notch target genes the in Enhancer of Split (E(spl)) complex, with E(spl)mδ being most responsive in vivo.
We next found that E(spl)mδ expression localizes to developing somatic muscles in embryos, and developing flight muscles in adult flies. With a genome wide association analysis, using the Drosophila Genetics Reference Panel (DGRP) (MacKay et al., 2012 Nature 482:173), we have now resolved several core genes in muscle and neuromuscular development pathways that associate with MeHg tolerance and susceptibility. Among the gene candidates are Kin of Irre (Kirre, the vertebrate KIRREL homolog) and Sticks and Stones (SNS, the vertebrate Nephrin homolog), heterotypic IgG adhesion binding partners that mediate myoblast fusion.
Using development of adult indirect flight muscles (IFMs) during the pupal stage as a model, we see that induced E(spl)mδ expression in transgenic flies shows MeHg-like phenotypes, while knockdown of E(spl)mδ spares flies from MeHg toxicity. We also find, using the C2C12 mouse myoblast culture model, that brief exposure to MeHg causes a persistent inhibition of the potential to differentiate to myotubes. Our studies continue to characterize the susceptibility of muscle targets in flies and we are now investigating conserved mechanisms in developing mice.
