Trends in Neurosciences
Feature ReviewSpecial Issue: Circuit Development and RemodelingPreserve and protect: maintaining axons within functional circuits
Section snippets
Establishing and maintaining circuits
Functional neural circuits depend on proper interconnections formed by long-range axonal projections. As the fundamental connective unit of neural circuits, axons must be protected and maintained in the face of multiple potential threats. Axonal maintenance is particularly important because most neurons cannot be replaced and must therefore be preserved throughout the life of the organism. Axon degeneration is a broad term applied to various modes of axon death, with distinct instigators but
Developmental axon preservation
A common theme in neural development is overproduction followed by elimination and refinement. This mechanism allows for great flexibility in potential circuit configuration [7]. In both the central and peripheral nervous systems, neurons initially extend excess axonal connections, and refinement into a mature circuit requires coordinated pruning of inappropriate connections and preservation of appropriate connections. Pruning must therefore be induced in a selective subset of axons while the
Developmental axon pruning
Axons or axonal segments that are not selected to survive can be eliminated by three distinct mechanisms (Figure 2A–C). The most well studied is axon degeneration, which culminates in cytoskeletal degradation, axon fragmentation, and removal of debris by glia and possibly epidermal cells (Figure 2A) 6, 7, 8, 11, 12, 35. By contrast, both axon retraction (Figure 2B) and axosome shedding (Figure 2C) have only been observed during small-scale pruning of synapses or terminal branches. Axon
Lifelong axon maintenance
Numerous mechanisms control the health and homeostasis of axons throughout life and oppose stressors such as excitation and aging. Injury and disease induce axon degeneration both by compromising maintenance mechanisms and promoting active self-destruction pathways. Expression of the Wallerian degeneration slow (WldS) mutant protein, a chimeric fusion of the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) and a fragment of the ubiquitination factor E4B
Pathological axon degeneration
Axons damaged by injury or disease must be actively eliminated. In some cases, removal of damaged axons enables axon regrowth and maintains neural circuitry, such as following lesions of peripheral axons. However, when axon trauma is more widespread or axons are not capable of regenerating, pathological axon degeneration compromises neural circuit functionality.
Following nerve transection, axons undergo Wallerian degeneration (Figure 2D). During an initial latency stage, the injured axon
Concluding remarks and future directions
The establishment and functionality of neural networks requires precise control of axon survival and elimination in development and throughout life. Recent studies describe core mechanisms that preserve connections between cells in a circuit and eliminate surplus or damaged connections. The mechanisms that govern axon survival and elimination have similarities to and differences from cell soma viability and death. In particular, interdependent mitochondrial and cytoskeletal processes are
Acknowledgments
Our research is supported by the National Institutes of Health grant R01NS050674, the Barr Weaver Award, and the Harvard/Massachusetts Institute of Technology (MIT) Joint Research Grant in Basic Neuroscience to R.A.S., and by the Edward R. and Anne G. Lefler Center Predoctoral Fellowship to S.E.P. We thank Dr Katharina Cosker, Sara Fenstermacher, and Maria Pazyra-Murphy for critical reading of the manuscript.
Glossary
- Apaf-1 (apoptotic protease activating factor 1)
- a key constituent of the apoptotic machinery that binds cytochrome c and subsequently activates caspase-9.
- Bcl-w (Bcl-2-like protein 2)
- a pro-survival Bcl-2 family member that binds pro-apoptotic Bcl-2 family members to prevent initiation of the axonal apoptotic caspase cascade [4].
- Calpains
- a family of calcium-activated cysteine proteases that degrade cytoskeletal components and are activated in both developmental and pathological axon degeneration
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Cited by (32)
Calpain-dependent truncated form of TrkB-FL increases in neurodegenerative processes
2016, Molecular and Cellular NeuroscienceCitation Excerpt :An increase in BDNF and proBDNF binding to p75ntr was also observed, a common characteristic of SE (Unsain et al., 2008) (Fig. 3I and J). Neuronal degeneration is a common feature of several neurological diseases (Luo and O'Leary, 2005; Liu et al., 2008; Bevers and Neumar, 2008; Pease and Segal, 2014). Also, it has been demonstrated that the decrease in TrkB-FL is a key early event preceding neuronal death (Unsain et al., 2008; Vidaurre et al., 2012; Jerónimo-Santos et al., 2015).
Axon degeneration: Context defines distinct pathways
2016, Current Opinion in NeurobiologyCitation Excerpt :While the mechanisms regulating the survival and elimination of neurons via apoptosis are well studied, the pathways governing the selective degeneration of the axons are less understood. Axon degeneration has been observed to occur in many contexts (e.g. pruning, axotomy, apoptosis, dying back) and models (e.g. D. melanogaster, C. elegans, mice), which has been discussed in several recent reviews [2,3,4,5,6]. In the mammalian model, mechanistic details of axon degeneration has been predominantly studied in vitro in three contexts: 1) Axotomy (also known as Wallerian degeneration), where the severing of axons results in the degeneration of axons distal to the cut site; 2) Apoptosis-induced Axon Degeneration, which we define here as ‘Axon Apoptosis’, where the entire neuron is exposed to apoptotic stimuli (e.g. global deprivation of trophic factors) resulting in the degeneration of both axons and soma; and 3) Pruning-induced Axon Degeneration, which we refer to here as ‘Axon Pruning’, where a subset of axons are selectively exposed to a pruning stimuli (e.g. axon-only or ‘local’ deprivation of trophic factors) which results in the selective degeneration of only the axons exposed to the stimulus.