The Role of Apoptotic Signaling in Axon Guidance

Abstract

Navigating growth cones are exposed to multiple signals simultaneously and have to integrate competing cues into a coherent navigational response. Integration of guidance cues is traditionally thought to occur at the level of cytoskeletal dynamics. Drosophila studies indicate that cells exhibit a low level of continuous caspase protease activation, and that axon guidance cues can activate or suppress caspase activity. We base a model for axon guidance on these observations. By analogy with other systems in which caspase signaling has non-apoptotic functions, we propose that caspase signaling can either reinforce repulsion or negate attraction in response to external guidance cues by cleaving cytoskeletal proteins. Over the course of an entire trajectory, incorrectly navigating axons may pass the threshold for apoptosis and be eliminated, whereas axons making correct decisions will survive. These observations would also explain why neurotrophic factors can act as axon guidance cues and why axon guidance systems such as Slit/Robo signaling may act as tumor suppressors in cancer.

Long‐distance regressive signaling in neural development and disease

“…Axon guidance cues have also been described to continue to function after target innervation. For example, repulsive axon guidance cues like semaphorin 3a (sema3a), Slit‐Robo and Eph‐Ephrins have been associated with cell death in multiple cell types after target innervation (Dickinson, Fegan, Ren, Hillier, & Duncan, 2011; Gagliardini & Fankhauser, 1999; Kellermeyer, Heydman, Mastick, & Kidd, 2018; H. Lee, Park, Kang, & Park, 2015; Wehner et al, 2016). Presumably, this is a way in which neurons innervating incorrect targets can be rapidly removed from a pool competing for neurotrophic factors derived from correct targets.…”

“…Long‐distance regressive signaling has also been observed or suggested with axon guidance cue‐receptor pairs including semaphorin‐Neuropilin/Plexin, Slit‐Robo, Netrin‐deleted in colorectal carcinoma (DCC)/UNC‐5, and Eph‐Ephrin (Hamasaki et al, 2001; Kellermeyer et al, 2018; Marín et al, 2003; Wehner et al, 2016; Yue et al, 1999). Neurons are exposed to these repulsive cues at intermediate and final targets.…”

“…There is growing evidence that receptors associated with growth cone attraction or repulsion are coupled to anti‐caspase or pro‐caspase activity. This has been proposed to be a mechanism to some axon guidance cue inputs resulting in attraction or repulsion (Kellermeyer et al, 2018). Caspase activity at distal axons is thought to be sub‐lethal, and repulsive cues have largely been thought to act locally at the site of ligand receptor engagement.…”

Recombinant human growth hormone treatment of mice suppresses inflammation and apoptosis caused by skin flap ischemia–reperfusion injury

“…Apoptosis is one of the processes of programmed cell death and is regulated by many genes and proteins . Studies have shown that apoptosis plays an important role in the process of IR injury .…”

“…12,13 Apoptosis is one of the processes of programmed cell death and is regulated by many genes and proteins. 14 Studies have shown that apoptosis plays an important role in the process of IR injury. 15 Apoptosis in the early reperfusion was found in clinical specimens and in animal models of flap IR injury 16,17 and apoptosis-related proteins play an important role in the process of apoptosis.…”