XIAP Regulates Caspase Activity in Degenerating Axons

Our knowledge of the destructive events that regulate axonal degeneration is rudimentary. Here, we examine the role of caspases and their endogenous inhibitor, the X-linked inhibitor of apoptosis protein (XIAP), in axonal degeneration of dorsal root ganglion (DRG) axons. We show that caspase-3, caspase-6, and caspase-9 are present in axons and are cleaved upon nerve growth factor (NGF) withdrawal. We observed that caspase-3 activity is high in NGF-withdrawn axons and that CASP3−/− axons are protected from degeneration. XIAP−/− DRG sensory neurons degenerate more rapidly and contain more active caspase-3 than their wild-type counterparts, indicating that axonal caspases are normally regulated by XIAP. Importantly, axonal XIAP levels drop sharply after NGF withdrawal; if XIAP levels are maintained by overexpression, axonal caspase-3 activation and axonal degeneration are suppressed. Finally, we show that XIAP−/− embryos have stunted dermal innervation. We propose that XIAP-mediated caspase inhibition plays an important role in regulating morphogenic events that shape the nervous system during development. [Display omitted] •Caspase-3 and caspase-9 play crucial roles in developmental axon degeneration•XIAP regulates caspase activity in degenerating neurites•XIAP levels must be reduced for axonal degeneration to proceed•An IAP-caspase regulatory loop regulates neurite degeneration across phylogeny Neuronal processes are actively removed during development by the localized, sublethal activity of caspases. The mechanism by which axons are able to control such actions is not known. Here, Barker and colleagues show that XIAP functions to suppress caspase-3 activity in intact axons and demonstrate that it must be removed by proteosomal activity for degeneration to proceed. Mice lacking XIAP display neuronal pruning defects in vivo, indicating that the XIAP-caspase loop normally sculpts sublethal morphogenetic changes in the nervous system.