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: David J Simon, Robby M Weimer, Todd McLaughlin, Dara Kallop, Karen Stanger, Jing Yang, Dennis D M O'Leary, Rami N Hannoush, Marc Tessier-Lavigne
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 32 Issue 49 Pg. 17540-53 (Dec 05 2012) ISSN: 1529-2401 [Electronic] United States
• PMID: 23223278 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• Nerve Growth Factor
• Caspase 3
• Caspase 6

Topics

• Animals
• Axons (enzymology, pathology, ultrastructure)
• Caspase 3 (genetics, physiology)
• Caspase 6 (genetics, physiology)
• Cells, Cultured
• Enzyme Activation (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Imaging (methods)
• Nerve Degeneration (enzymology, genetics, pathology)
• Nerve Growth Factor (adverse effects)
• Proto-Oncogene Proteins c-bcl-2 (physiology)
• Sensory Receptor Cells (enzymology, pathology)
• Signal Transduction (genetics, physiology)
• Superior Colliculi (enzymology, growth & development)
• Wallerian Degeneration (enzymology, genetics, pathology)
• bcl-2-Associated X Protein (genetics, physiology)