title: XIAP regulates caspase activity in degenerating axons.
abstract: 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 We observed that caspase-3 activity is high in NGF-withdrawn axons and that CASP3(-/-) axons are protected from degeneration.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.
authors: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
authors: Nicolas
authors: N
authors: Unsain
authors: Julia M
authors: JM
authors: Higgins
authors: Kristen N
authors: KN
authors: Parker
authors: Aaron D
authors: AD
authors: Johnstone
authors: Philip A
authors: PA
authors: Barker
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059748:Proteolysis; D012867:Skin / Q000294:innervation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; D020169:Caspases