Portal de Periódicos da CAPES

A Caspase Cascade Regulating Developmental Axon Degeneration

2012; Society for Neuroscience; Volume: 32; Issue: 49 Linguagem: Inglês

10.1523/jneurosci.3012-12.2012

1529-2401

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,

Axon Guidance and Neuronal Signaling

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.