Trends in Neurosciences
Volume 37, Issue 10, October 2014, Pages 572-582
Journal home page for Trends in Neurosciences

Feature Review
Special Issue: Circuit Development and Remodeling
Preserve and protect: maintaining axons within functional circuits

https://doi.org/10.1016/j.tins.2014.07.007Get rights and content

Highlights

  • Pro-survival molecules protect axons from developmental pruning.

  • Apoptotic machinery mediates axonal pruning during development.

  • Lifelong axon maintenance requires proper mitochondrial and cytoskeletal function.

  • Impaired axon maintenance results in pathological axon degeneration.

During development, neural circuits are initially generated by exuberant innervation and are rapidly refined by selective preservation and elimination of axons. The establishment and maintenance of functional circuits therefore requires coordination of axon survival and degeneration pathways. Both developing and mature circuits rely on interdependent mitochondrial and cytoskeletal components to maintain axonal health and homeostasis; injury or diseases that impinge on these components frequently cause pathologic axon loss. Here, we review recent findings that identify mechanisms of axonal preservation in the contexts of development, injury, and disease.

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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