A Caspase Cascade Regulating Developmental Axon Degeneration

• DOI: 10.1523/jneurosci.3012-12.2012
• Publication Date: 2012-12-05T17:46:54Z
• 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
• Keywords: Mice, Knockout; 0301 basic medicine; Superior Colliculi; Caspase 6; Sensory Receptor Cells; Caspase 3; Axons; Molecular Imaging; Enzyme Activation; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Nerve Degeneration; Nerve Growth Factor; Animals; Wallerian Degeneration; Cells, Cultured; Signal Transduction; bcl-2-Associated X Protein

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 ofCaspase-6indeed 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 ofCaspase-3is 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-3andCaspase-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.