dSarm/Sarm1 is required for activation of an injury-induced axon death pathway.
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.
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Jeannette M
JM
Osterloh
Jing
J
Yang
Timothy M
TM
Rooney
A Nicole
AN
Fox
Robert
R
Adalbert
Eric H
EH
Powell
Amy E
AE
Sheehan
Michelle A
MA
Avery
Rachel
R
Hackett
Mary A
MA
Logan
Jennifer M
JM
MacDonald
Jennifer S
JS
Ziegenfuss
Stefan
S
Milde
Ying-Ju
YJ
Hou
Carl
C
Nathan
Aihao
A
Ding
Robert H
RH
Brown
Laura
L
Conforti
Michael
M
Coleman
Marc
M
Tessier-Lavigne
Stephan
S
Züchner
Marc R
MR
Freeman
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D051186:Armadillo Domain Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D019771:Axotomy; D002470:Cell Survival; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D003714:Denervation; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries / Q000502:physiology; D015398:Signal Transduction; D017783:Superior Cervical Ganglion / Q000166:cytology; D046509:Tissue Culture Techniques; D014855:Wallerian Degeneration
D051186:Armadillo Domain Proteins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; C574122:Ect4 protein, Drosophila; C543961:SARM1 protein, mouse