Mechanisms of Methylmercury Toxicity in Neuromuscular Development

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 DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a persistent environmental toxicant that has long been understood to target the developing nervous system. Understanding the risks of MeHg versus the benefits of essential nutrients that come with eating fish requires a greater understanding of the mechanisms by which MeHg induces neurological deficits during development. Fetal MeHg exposure can elicit both motor and cognitive deficits in infants and young children. Yet, the possibility that motor deficits stem from altered muscle development has been largely overlooked. In this proposal we will characterize an apparent role of embryonic muscle as a MeHg target, thereby extending the fundamental domain of MeHg neurotoxicity to the developing motor unit. This study is guided by our earlier discoveries in Drosophila that MeHg can activate developmental signaling through the Notch receptor pathway, specifically up-regulating the Notch target gene enhancer of split mDelta (E(spl)mδ). We also find that MeHg has a propensity to disrupt muscle development in the embryo in parallel with its effects on developing motor neurons. We now show that E(spl)mδ is intrinsically expressed in the embryonic mesoderm and myogenic lineages and that, akin to MeHg exposure, enhanced E(spl)mδ expression in the embryo induces a somatic muscle phenotype and corresponding defects in motor neuron outgrowth. Through a genome wide association analysis (GWA) we have uncovered numerous fundamental muscle development genes that associate with tolerance to MeHg, notably, the Kirre cell adhesion protein, a core component of myoblast fusion in myofibril formation. Thus, our overall hypothesis is that MeHg perturbation of myogenesis contributes to abnormal neuromuscular development leading to motor deficits. This hypothesis poses several fundamental questions that we will address through four Specific Aims. In Aim 1 we will determine the fundamental role of myogenesis as a MeHg target in neuromuscular development in the embryo. In Aim 2 we characterize further the role of Notch signaling as an adverse outcome pathway of MeHg toxicity in neuromuscular development. For Aim 3 we will interrogate the function of the myoblast fusion protein Kirre as moderator of MeHg effects on myoblast fusion in neuromuscular development. In Aim 4 we translate our findings to the mouse and investigate mammalian corollaries for muscle-intrinsic defects in cultured myoblasts and prenatally MeHg-exposed mice. In sum, this study will significantly advance the current understanding of how motor deficits are likely to arise from early life MeHg exposure and thereby inform both the experimental toxicologist and the clinician on the potential for a myopathic component of MeHg neurotoxicity.