Open AccessTissue-specific Nrf2 signaling protects against methylmercury toxicity in Drosophila neuromuscular development
Author(s) -
Jakob Gunderson,
Ashley E. Peppriell,
Daria Vorojeikina,
Matthew D. Rand
Publication year - 2020
Publication title -
archives of toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.264
H-Index - 111
eISSN - 1432-0738
pISSN - 0340-5761
DOI - 10.1007/s00204-020-02879-z
Subject(s) - gene knockdown , downregulation and upregulation , keap1 , microbiology and biotechnology , chemistry , toxicity , biology , neuroscience , biochemistry , transcription factor , gene , organic chemistry
Methylmercury (MeHg) can elicit cognitive and motor deficits due to its developmental neuro- and myotoxic properties. While previous work has demonstrated that Nrf2 antioxidant signaling protects from MeHg toxicity, in vivo tissue-specific studies are lacking. In Drosophila, MeHg exposure shows greatest developmental toxicity in the pupal stage resulting in failed eclosion (emergence of adults) and an accompanying 'myosphere' phenotype in indirect flight muscles (IFMs). To delineate tissue-specific contributions to MeHg-induced motor deficits, we investigated the potential of Nrf2 signaling in either muscles or neurons to moderate MeHg toxicity. Larva were exposed to various concentrations of MeHg (0-20 µM in food) in combination with genetic modulation of the Nrf2 homolog cap-n-collar C (CncC), or its negative regulator Keap1. Eclosion behavior was evaluated in parallel with the morphology of two muscle groups, the thoracic IFMs and the abdominal dorsal internal oblique muscles (DIOMs). CncC signaling activity was reported with an antioxidant response element construct (ARE-GFP). We observed that DIOMs are distinguished by elevated endogenous ARE-GFP expression, which is only transiently seen in the IFMs. Dose-dependent MeHg reductions in eclosion behavior parallel formation of myospheres in the DIOMs and IFMs, while also increasing ARE-GFP expression in the DIOMs. Modulating CncC signaling via muscle-specific Keap1 knockdown and upregulation gives a rescue and exacerbation, respectively, of MeHg effects on eclosion and myospheres. Interestingly, muscle-specific CncC upregulation and knockdown both induce lethality. In contrast, neuron-specific upregulation of CncC, as well as Keap1 knockdown, rescued MeHg effects on eclosion and myospheres. Our findings indicate that enhanced CncC signaling localized to either muscles or neurons is sufficient to rescue muscle development and neuromuscular function from a MeHg insult. Additionally, there may be distinct roles for CncC signaling in myo-morphogenesis.