Methylmercury (MeHg) is a ubiquitous, developmental neurotoxicant capable of eliciting cognitive and motor deficits in children. The presentation of motor deficits suggests that MeHg acts on neuronal and muscle derived targets in the developing neuromuscular system, and potentially the neuromuscular junction (NMJ). Our lab has established the neuromuscular behaviors of eclosion and flight as sensitive, functional outputs of MeHg toxicity, such that MeHg induces both eclosion and flight deficits. We hypothesize that the decrease in eclosion and flight ability could be in part due to MeHg disrupting NMJ development. A previously conducted genome wide association study (GWAS) using Drosophila revealed several NMJ-associated gene variants that accompanied a muscle phenotype of myospheres in the indirect flight muscles (IFM). By assessing morphological and functional phenotypes of adult structures formed during metamorphosis following larval exposure to MeHg, we explored the exisitence of muscle derived MeHg targets that might act in conjunction with neural targets at the NMJ. The IFM neuromuscular morphology was visualized using fluorescent reporter fly strains and neuromuscular function was assessed via eclosion and flight behavior. The Nrf2 antioxidant pathway is a recognized protective mechanism to MeHg. Drosophila melanogaster contains an analogous inducible antioxidant pathway, the CncC pathway. Through an ARE-GFP reporter, we show that the either exposure to MeHg or transgenic knockdown of CncCâs negative regulator, Keap1, activates the endogenous CncC pathway. Transgenic enhancement of CncC pathway activity in either muscle or neural lineages during development moderates MeHg toxicity, seen by reduction in IFM myospheres and a rescue in eclosion and flight ability. These results indicate that both the developing muscle and motor neurons contribute to the MeHg-induced phenotypes. Furthermore, developmental MeHg exposure reduces the extent of IFM innervation. This prompted us to further explore a role for the NMJ mediating the impact of MeHg on neuromuscular events. Neuroligin 1 (Nlg1), an identified GWAS candidate, is a muscle-restricted, NMJ-associated cell adhesion factor and the heterodimeric synpatic partner of neurexin-1 (Nrx1), which is required for both axonal arborization and NMJ maturation. Relative to other Nlg and Nrx members, nlg1 expression is selectivity repressed early in pupal metamorphosis by MeHg. Temporally restricting nlg1 knockdown to the same developmental window as MeHg also reduces flight ability. Whereas muscle-specific overexpression of nlg1 partially rescues MeHg-mediated deficits in both eclosion and flight. These findings indicate that tissue-specific antioxidant signaling can moderate MeHg toxicity, that both developing muscle and neurons are targets of MeHg, provides evidence for the developing NMJ being a MeHg target, and highlights Nlg1 as a partial mediator of MeHg toxicity. More broadly, this work continues to demonstrate that MeHg interacts with discrete cellular targets during development and targeted research into these factors may reveal therapies or mechanisms by which to protect the developing fetus from MeHg toxicity.