Neuroligin-1 Is a Mediator of Methylmercury Neuromuscular Toxicity

Abstract

Methylmercury (MeHg) is a developmental toxicant capable of eliciting neurocognitive and neuromuscular deficits in children with in utero exposure. Previous research in Drosophila melanogaster uncovered that developmental MeHg exposure simultaneously targets the developing musculature and innervating motor neuron in the embryo, along with identifying Drosophila neuroligin 1 (nlg1) as a gene associated with developmental MeHg sensitivity. Nlg1 and its transsynaptic partner neurexin 1 (Nrx1) are critical for axonal arborization and NMJ maturation. We investigated the effects of MeHg exposure on indirect flight muscle (IFM) morphogenesis, innervation, and function via flight assays and monitored the expression of NMJ-associated genes to characterize the role of Nlg1 mediating the neuromuscular toxicity of MeHg. Developmental MeHg exposure reduced the innervation of the IFMs, which corresponded with reduced flight ability. In addition, nlg1 expression was selectively reduced during early metamorphosis, while a subsequent increase was observed in other NMJ-associated genes, including nrx1, in late metamorphosis. Developmental MeHg exposure also resulted in persistent reduced expression of most nlg and nrx genes during the first 11 days of adulthood. Transgenic modulation of nlg1 and nrx1 revealed that developing muscle is particularly sensitive to nlg1 levels, especially during the 20 – 36-hour window of metamorphosis with reduced nlg1 expression resulting in adult flight deficits. Muscle-specific overexpression of nlg1 partially rescued MeHg-induced deficits in eclosion and flight. We identified Nlg1 as a muscle-specific, NMJ structural component, that can mediate MeHg neuromuscular toxicity resulting from early life exposure.

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science

“…Behavioral assays for toxicity in larvae include crawling speed, chemotaxis, phototaxis, and avoidance behavior (Aleman‐Meza et al., 2015; Gerber & Stocker, 2007; Gerber et al., 2009). Tests of adult fly behaviors are continually being developed to assess complex behaviors (Moulin et al., 2021) for toxicity testing including locomotor activity, climbing, flight, and longevity, all of which are quantifiable (Gunderson et al., 2021; Peppriell et al., 2021). More elaborate behaviors such as mating and fecundity (Tiwari et al., 2011), food choice (El Kholy & Al Naggar, 2023), and even associative learning and memory (Zamberlan et al., 2020) are available to assess toxicity.…”