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Science 337 (6093): 481-484

Copyright © 2012 by the American Association for the Advancement of Science

dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway

Jeannette M. Osterloh,1 Jing Yang,2 Timothy M. Rooney,1 A. Nicole Fox,1 Robert Adalbert,4 Eric H. Powell,3 Amy E. Sheehan,1 Michelle A. Avery,1 Rachel Hackett,1,* Mary A. Logan,1,{dagger} Jennifer M. MacDonald,1 Jennifer S. Ziegenfuss,1 Stefan Milde,4 Ying-Ju Hou,5 Carl Nathan,5 Aihao Ding,5 Robert H. Brown, Jr.,6 Laura Conforti,7 Michael Coleman,4 Marc Tessier-Lavigne,2 Stephan Züchner,3 Marc R. Freeman1,*,{ddagger}

Abstract: 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 α/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.

1 Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2 Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
3 John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
4 Babraham Institute, Cambridge CB22 3AT, UK.
5 Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
6 Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
7 School of Biomedical Sciences, University of Nottingham Medical School Queen’s Medical Centre, Nottingham, NG7 2UH, UK.

* Howard Hughes Medical Institute, Chevy Chase, MD 20815–6789, USA.

{dagger} Present address: Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.

{ddagger} To whom correspondence should be addressed. E-mail: marc.freeman{at}umassmed.edu


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