The Notch target E(spl)mδ is a muscle-specific gene involved in methylmercury toxicity in motor neuron development

Methylmercury (MeHg) is a ubiquitous environmental toxin that has a selective and potent impact on the nervous system, particularly during neural development yet, the mechanisms for its apparent neurodevelopmental specificity are unknown. The Notch receptor pathway has been implicated as a MeHg target in several studies. Notch signaling mediates cell-cell signals in a number of developmental contexts including neurogenesis and myogenesis, where it fundamentally acts to repress differentiation. Previous work in our lab has shown that MeHg causes preferential upregulation of a canonical Notch response gene, E(spl)m delta, in Drosophila embryos. In parallel, MeHg is seen to disrupt outgrowth of embryonic intersegmental motor nerves (ISN), which can be mimicked by expression of activated Notch in embryonic neurons. However, overexpression of E(spl)m delta in developing neurons fails to elicit motor neuron outgrowth defects, pointing to a non-autonomous role for E(spl)m delta in motor axon development. In this study we investigate a role for E(spl)m delta in conveying the toxicity of MeHg in the embryo. We find that endogenous expression of the E(spl)m delta gene localizes to developing somatic muscles in embryos. Notably, E(spl)m delta expression is seen in several muscles that are known synaptic targets for both the ISN and the segmental motor nerve (SN). We also demonstrate that the SN, similar to the ISN, exhibits disrupted axon outgrowth in response to MeHg. E(spl)m delta can induce a SN motor neuron phenotype, similar to MeHg treatment; but, only when E(spl)m delta expression is targeted to developing muscles. E(spl)m delta overexpression in developing muscles also results in aberrant muscle morphology, which is not apparent with expression of the closely related E(spl)m gamma in developing muscles. Our data point to a role for the Notch target E(spl)m delta in mediating MeHg toxicity in embryonic development by disrupting the coordinated targeting of motor neurons to their muscle targets. (C) 2014 Elsevier Inc. All rights reserved.