dSarm/Sarm1 is required for activation of an injury-induced axon death pathway
Department of Neurobiology; Department of Neurology; Freeman Lab; Graduate School of Biomedical Sciences, Neuroscience Program; Graduate School of Biomedical Sciences, MD/PhD Program
Medical Subject Headings
Animals; Animals, Genetically Modified; Apoptosis; Armadillo Domain Proteins; Axons; Axotomy; Cell Survival; Cells, Cultured; Cytoskeletal Proteins; Denervation; Drosophila; Drosophila Proteins; Mice; Mutation; Neurons; Sciatic Nerve; Signal Transduction; Superior Cervical Ganglion; Tissue Culture Techniques; *Wallerian Degeneration
Neuroscience and Neurobiology
Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Here, we show that loss of the Drosophila Toll receptor adaptor dSarm (sterile alpha/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway.
Osterloh, Jeannette M.; Yang, Jing; Rooney, Timothy M.; Fox, A. Nicole; Adalbert, Robert; Powell, Eric H.; Sheehan, Amy E.; Avery, Michelle A.; Hackett, Rachel; Logan, Mary A.; MacDonald, Jennifer M.; Ziegenfuss, Jennifer S.; Milde, Stefan; Hou, Ying-Ju; Nathan, Carl; Ding, Aihao; Brown, Robert H. Jr.; Comforti, Laura; Coleman, Michael; Tessier-Lavigne, Marc; Zuchner, Stephan; and Freeman, Marc R., "dSarm/Sarm1 is required for activation of an injury-induced axon death pathway" (2012). GSBS Student Publications. 1789.