Elsevier

Neuroscience Research

Volume 139, February 2019, Pages 3-8
Neuroscience Research

Review article
Apoptosis versus axon pruning: Molecular intersection of two distinct pathways for axon degeneration

https://doi.org/10.1016/j.neures.2018.11.007Get rights and content

Highlights

  • Neuronal apoptosis and axon pruning engage distinct pathways to mediate axon degeneration.

  • Apoptosis and axon pruning both involve DLK/JNK signaling, Puma and Bax.

  • Apoptosis requires caspases (Casp9, Casp3) that are activated via the Apaf-1 apoptosome.

  • Axon pruning requires Casp9, Casp3, and also Casp6, but not the Apaf-1 apoptosome.

Abstract

Neurons are capable of degenerating their axons for the physiological clearance and refinement of unnecessary connections via the programmed degenerative pathways of apoptosis and axon pruning. While both pathways mediate axon degeneration they are however distinct. Whereas in apoptosis the entire neuron, both axons and cell body, degenerates, in the context of axon pruning only the targeted axon segments are selectively degenerated. Interestingly, the molecular pathways mediating axon degeneration in these two contexts have significant mechanistic overlap but also retain distinct differences. In this review, we describe the peripheral neuronal cell culture models used to study the molecular pathways of apoptosis and pruning. We outline what is known about the molecular mechanisms of apoptosis and axon pruning and focus on highlighting the similarities and differences of these two pathways.

Section snippets

Introduction to neuronal apoptosis and axon pruning

Neuronal apoptosis occurs extensively and plays a critical role during the development of the nervous system (Burek and Oppenheim, 1996). During nervous system development neurons are produced in excess to ensure productive connections are made to the appropriate targets. Neurons that are unable to successfully innervate their targets, or are no longer necessary, are selectively eliminated by the activation of the apoptotic pathway. This selective elimination of non-productive neurons ensures

Compartmentalized chambers to investigate the molecular pathways of apoptosis versus axon pruning

The model system most frequently used to study the molecular pathways of neuronal apoptosis and axon pruning are developing peripheral neurons (e.g. sympathetic neurons, Dorsal Root Ganglion neurons) in the context of NGF deprivation (Geden and Deshmukh, 2016; Kristiansen and Ham, 2014). Neurons globally deprived of NGF (from both soma and axons) activate the apoptotic pathway which results in the death and degeneration of the entire cell, both soma and axons. Indeed, NGF deprivation of

Molecular pathway of neuronal apoptosis

The key mediators of apoptosis are caspases, a family of cysteine proteases that cleave specific cellular substrates to cause rapid cell death (Denault and Salvesen, 2002)(Fig. 2). In sympathetic neurons undergoing apoptosis due to NGF deprivation, the mechanism by which caspases are activated has been well-studied and is known to occur via the mitochondrial (intrinsic) pathway (Fricker et al., 2018; Kristiansen and Ham, 2014). NGF deprivation results in decreased signaling from the survival

Molecular pathway of axon pruning

The apoptosis and axon pruning pathways share many of the same proteins but with key differences that are highlighted here (Fig. 2). It is crucial to note here that while both apoptosis and axon pruning can be triggered in peripheral neurons with NGF deprivation, the context of NGF deprivation is essential to consider as it results in the engagement of distinct pathways. Whereas apoptosis is engaged in the context of global deprivation of entire neuron (both soma and axons), axon pruning is

Acknowledgement

This work was supported by grant from National Institutes of Health (GM118331) to MD.

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