Signaling mechanisms regulating Wallerian degeneration

•The chimeric WldS molecule revealed axons can survive for long periods without a cell body.•WldS raised the intriguing possibility that axon degeneration is an active process.•WldS functional domains are now defined, but its mechanistic action remains unclear.•dSarm/Sarm1 and Hiw/Phr1 are endogenous genes required to drive axon degeneration.•'Axon death' pathways therefore exist, and may be relevant to neurological disease.

Wallerian degeneration (WD) occurs after an axon is cut or crushed and entails the disintegration and clearance of the severed axon distal to the injury site. WD was initially thought to result from the passive wasting away of the distal axonal fragment, presumably because it lacked a nutrient supply from the cell body. The discovery of the slow Wallerian degeneration (Wlds) mutant mouse, in which distal severed axons survive intact for weeks rather than only one to two days, radically changed our thoughts on the autonomy of axon survival. Wlds taught us that under some conditions the axonal compartment can survive for weeks after axotomy without a cell body. The phenotypic and molecular characterization of WldS and current models for WldS molecular function are reviewed herein - the mechanism(s) by which WldS spares severed axons remains unresolved. However, recent studies inspired by Wlds have led to the identification of the first 'axon death' signaling molecules whose endogenous activities promote axon destruction during WD.