title: A caspase cascade regulating developmental axon degeneration.
abstract: Axon degeneration initiated by trophic factor withdrawal shares many features with programmed cell death, but many prior studies discounted a role for caspases in this process, particularly Caspase-3. Recently, Caspase-6 was implicated based on pharmacological and knockdown evidence, and we report here that genetic deletion of Caspase-6 indeed provides partial protection from degeneration. However, we find at a biochemical level that Caspase-6 is activated effectively only by Caspase-3 but not other "upstream" caspases, prompting us to revisit the role of Caspase-3. In vitro, we show that genetic deletion of Caspase-3 is fully protective against sensory axon degeneration initiated by trophic factor withdrawal, but not injury-induced Wallerian degeneration, and we define a biochemical cascade from prosurvival Bcl2 family regulators to Caspase-9, then Caspase-3, and then Caspase-6. Only low levels of active Caspase-3 appear to be required, helping explain why its critical role has been obscured in prior studies. In vivo, Caspase-3 and Caspase-6-knockout mice show a delay in developmental pruning of retinocollicular axons, thereby implicating both Caspase-3 and Caspase-6 in axon degeneration that occurs as a part of normal development.
authors.affiliation: Laboratory of Brain Development and Repair, Rockefeller University, New York, New York 10065, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Simon
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.forename: Todd
authors.initials: T
authors.lastname: McLaughlin
authors.forename: Dara
authors.initials: D
authors.lastname: Kallop
authors.forename: Karen
authors.initials: K
authors.lastname: Stanger
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Dennis D M
authors.initials: DD
authors.lastname: O'Leary
authors.forename: Rami N
authors.initials: RN
authors.lastname: Hannoush
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D053148:Caspase 3 / Q000235:genetics / Q000502:physiology*; D053178:Caspase 6 / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057054:Molecular Imaging / Q000379:methods; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020932:Nerve Growth Factor / Q000009:adverse effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011984:Sensory Receptor Cells / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013477:Superior Colliculi / Q000201:enzymology / Q000254:growth & development*; D014855:Wallerian Degeneration / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000502:physiology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020932:Nerve Growth Factor; D053148:Caspase 3; D053178:Caspase 6