@article{aac78d4e506041f895ca69c34a6fa7cb,
title = "Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia",
abstract = "Nervous system injury and disease have broad effects on the functional connectivity of the nervous system, but how injury signals are spread across neural circuits remains unclear. We explored how axotomy changes the physiology of severed axons and adjacent uninjured “bystander” neurons in a simple in vivo nerve preparation. Within hours after injury, we observed suppression of axon transport in all axons, whether injured or not, and decreased mechano- and chemosensory signal transduction in uninjured bystander neurons. Unexpectedly, we found the axon death molecule dSarm, but not its NAD+ hydrolase activity, was required cell autonomously for these early changes in neuronal cell biology in bystander neurons, as were the voltage-gated calcium channel Cacophony (Cac) and the mitogen-activated protein kinase (MAPK) signaling cascade. Bystander neurons functionally recovered at later time points, while severed axons degenerated via α/Armadillo/Toll-interleukin receptor homology domain (dSarm)/Axundead signaling, and independently of Cac/MAPK. Interestingly, suppression of bystander neuron function required Draper/MEGF10 signaling in glia, indicating glial cells spread injury signals and actively suppress bystander neuron function. Our work identifies a new role for dSarm and glia in suppression of bystander neuron function after injury and defines two genetically and temporally separable phases of dSarm signaling in the injured nervous system.",
keywords = "Drosophila, Sarm1, Wallerian degeneration, axotomy, bystander effect, dSarm, nerve injury",
author = "Hsu, {Jiun Min} and Yunsik Kang and Corty, {Megan M.} and Danielle Mathieson and Peters, {Owen M.} and Freeman, {Marc R.}",
note = "Funding Information: We thank all the lab members of Freeman lab for the suggestions and discussions on this work and manuscript writing. We thank Dr. Richard Goodman in OHSU for sharing E. coli NMNd cDNA. We thank Dr. Li-Kroeger in Dr. Hugo Bellen's lab at Baylor College of Medicine for sharing pBH vector and helping with dsarmE1170A fly generation. We thank Dr. Lukas Neukomm at the University of Lausanne, Switzerland for sharing 5xUAS-Gal4 transgenic flies. We thank Dr. Kelly Monk for providing the microwave and assisting with electron microscopy (EM) fixation procedures, as well as Jo Hill and Sue Aicher for technical support with TEM. We thank Dr. Sean D. Speese for sharing the technology of imaging Ca2+ response after laser ablation on living animals. This study was supported by NIH P30 grant NS061800 to the OHSU Neuroscience Imaging Center, NIH RO1 grant NS059991 (to MRF), and OHSU. O.M.P. found the suppression of autophagosomes after injury. J.-M.H. and M.R.F. conceived and designed the research. J.-M.H. and Y.K. designed and generated dsarmE1170A allele. M.M.C. performed EM wing imaging. D.M. performed Ca2+ imaging after laser ablation. J.-M.H. performed all the rest of experiments. J.-M.H. and M.R.F. wrote the manuscript. M.R.F. is a co-founder of Nura Bio, whose goal is to block axon loss in disease. Funding Information: We thank all the lab members of Freeman lab for the suggestions and discussions on this work and manuscript writing. We thank Dr. Richard Goodman in OHSU for sharing E. coli NMNd cDNA. We thank Dr. Li-Kroeger in Dr. Hugo Bellen{\textquoteright}s lab at Baylor College of Medicine for sharing pBH vector and helping with dsarm E1170A fly generation. We thank Dr. Lukas Neukomm at the University of Lausanne, Switzerland for sharing 5xUAS-Gal4 transgenic flies. We thank Dr. Kelly Monk for providing the microwave and assisting with electron microscopy (EM) fixation procedures, as well as Jo Hill and Sue Aicher for technical support with TEM. We thank Dr. Sean D. Speese for sharing the technology of imaging Ca 2+ response after laser ablation on living animals. This study was supported by NIH P30 grant NS061800 to the OHSU Neuroscience Imaging Center, NIH RO1 grant NS059991 (to MRF), and OHSU . ",
year = "2021",
month = feb,
day = "3",
doi = "10.1016/j.neuron.2020.11.012",
language = "English (US)",
volume = "109",
pages = "473--487.e5",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "3",
}