Abstract
Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxicant that has long been known to cause a variety of motor deficits. These motor deficits have primarily been attributed to MeHg targeting of developing neurons and induction of oxidative stress and calcium dysregulation. Few studies have looked at how MeHg may be affecting fundamental signaling mechanisms in development, particularly in developing muscle. Studies in Drosophila recently revealed that MeHg perturbs embryonic muscle formation and upregulates Notch target genes, reflected predominantly by expression of the downstream transcriptional repressor Enhancer of Split mdelta [E(spl)mδ]. An E(spl)mδ reporter gene shows expression primarily in the myogenic domain, and both MeHg exposure and genetic upregulation of E(spl)mδ can disrupt embryonic muscle development. Here, we tested the hypothesis that developing muscle is targeted by MeHg via upregulation of E(spl)mδ using genetic modulation of E(spl)mδ expression in combination with MeHg exposure in developing flies. Developmental MeHg exposure causes a decreased rate of eclosion that parallels gross disruption of indirect flight muscle (IFM) development. An increase in E(spl) expression across the pupal stages, with preferential E(spl)mδ upregulation occurring at early (p5) stages, is also observed. E(spl)mδ overexpression in myogenic lineages under the Mef2 promoter was seen to phenocopy eclosion and IFM effects of developmental MeHg exposure; whereas reduced expression of E(spl)mδ shows rescue of eclosion and IFM morphology effects of MeHg exposure. No effects were seen on eclosion with E(spl)mδ overexpression in neural and gut tissues. Our data indicate that muscle development is a target for MeHg and that E(spl)mδ is a muscle-specific mediator of this myotoxicity. This research advances our knowledge of the target pathways that mediate susceptibility to MeHg toxicity, as well as a potential muscle development-specific role for E(spl)mδ.
Highlights
Methylmercury (MeHg) is one of the most toxic forms of mercury, which has been studied extensively for its properties as a developmental neurotoxicant (Clarkson et al, 2007)
We have previously shown that MeHg disrupts muscle development in Drosophila, both in embryos (Engel and Rand, 2014a) and in the indirect flight muscles (IFMs) during pupation (Montgomery et al, 2014)
To test whether muscle is being directly affected, independent of effects that MeHg may have on neurons, we attempted to genetically protect muscle lineage cells by targeted upregulation of the Multidrug Resistance Protein (MRP) using the GAL4UAS system (Figure 1A)
Summary
Methylmercury (MeHg) is one of the most toxic forms of mercury, which has been studied extensively for its properties as a developmental neurotoxicant (Clarkson et al, 2007). Among the wide range of neurological deficits that MeHg causes, several involve motor deficits which resemble cerebral palsy, including ataxia, muscle weakness, rigidity, abnormal muscle tone and reflexes, E(spl)mδ Mediates MeHg Myotoxicity and involuntary movements (McKeown-Eyssen et al, 1983; Harada, 1995; Roegge and Schantz, 2006). These motor deficits have primarily been attributed to MeHg targeting of neurons (Sager et al, 1982, 1984; Eto et al, 2010; Patel and Reynolds, 2013). When activated in muscle lineages, Notch signaling inhibits differentiation, and maintains progenitors and satellite cells by promoting quiescence and self-renewal (Vasyutina et al, 2007; Mourikis et al, 2012; Wen et al, 2012)
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