Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling

• Published in: Cell Vol. 164; no. 5; pp. 1031 - 1045
• Main Authors: Simon, David J., Pitts, Jason, Hertz, Nicholas T., Yang, Jing, Yamagishi, Yuya, Olsen, Olav, Tešić Mark, Milica, Molina, Henrik, Tessier-Lavigne, Marc
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.02.2016
• Subjects: Amino Acid Sequence; Animals; Apoptosis; Apoptosis Regulatory Proteins - chemistry; Apoptosis Regulatory Proteins - metabolism; Axons - metabolism; Axons - pathology; bcl-X Protein - metabolism; Mice; Molecular Sequence Data; Nerve Degeneration - pathology; Neurons - metabolism; Neurons - pathology; Proteins - metabolism; Signal Transduction; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.01.032

During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving axon degeneration upon local deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present in axons, the cell body is an active participant in gating axonal caspase activation and axon degeneration. Loss of trophic support in axons initiates retrograde activation of a somatic pro-apoptotic pathway, which, in turn, is required for distal axon degeneration via an anterograde pro-degenerative factor. At a molecular level, the cell body is the convergence point of two signaling pathways whose integrated action drives upregulation of pro-apoptotic Puma, which, unexpectedly, is confined to the cell body. Puma then overcomes inhibition by pro-survival Bcl-xL and Bcl-w and initiates the anterograde pro-degenerative program, highlighting the role of the cell body as an arbiter of large-scale axon removal. [Display omitted] •The cell body is an active and essential regulator of distal axon degeneration•The cell body integrates retrograde loss of Akt and gain of JNK signaling•Pro-apoptotic Puma in the cell body initiates an anterograde degenerative program Contrary to the notion that the decision of a sensory axon to degenerate occurs exclusively within the axon, new findings show that the cell body is an integration hub of pro-degenerative and pro-survival signals and gates distal axon degeneration.