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Branch management: mechanisms of axon branching in the developing vertebrate CNS

Nature Reviews Neuroscience volume 15, pages 7–18 (2014)Cite this article

Subjects

Key Points

  • Axon branching connects single neurons with multiple targets, which, along with the formation of highly branched terminal arbors, underlies the complex circuitry of the vertebrate CNS.

  • Axon collateral branches extend interstitially from the axon shaft as dynamic filopodia that develop into branches at appropriate targets regions to form functional maps. Extrinsic guidance cues, growth factors and morphogens regulate axon branching and shape terminal arbors that develop from axon branches.

  • Growth and guidance of axon branches in response to extracellular cues require dynamic reorganization of the actin and microtubule cytoskeleton. Cycles of cytoskeletal polymerization and depolymerization are highly regulated by actin- and microtubule-associated proteins during branch formation.

  • Complex signalling pathways that are activated by extracellular cues through their receptors regulate axon branching. The ultimate target of signal transduction pathways is the cytoskeleton, which can reorganize by changes in dynamics to promote or suppress axon branching.

  • Neuronal activity, which is often stimulated by extracellular cues, can regulate axon branching by transient fluctuations in the levels of intracellular calcium, which acts as a second messenger to activate downstream cytoskeletal effectors. Effects of neural activity can involve competition among neighbouring axon arbors, such as in the retinotectal system, where competitive activity-dependent mechanisms regulate arbor size and complexity.

  • Future directions in the study of axon branch formation will involve the use of preparations of the vertebrate CNS that recapitulate the complexity of the in vivo environment. Improvements in labelling techniques and high-resolution time-lapse microscopy should facilitate such studies.

Abstract

The remarkable ability of a single axon to extend multiple branches and form terminal arbors enables vertebrate neurons to integrate information from divergent regions of the nervous system. Axons select appropriate pathways during development, but it is the branches that extend interstitially from the axon shaft and arborize at specific targets that are responsible for virtually all of the synaptic connectivity in the vertebrate CNS. How do axons form branches at specific target regions? Recent studies have identified molecular cues that activate intracellular signalling pathways in axons and mediate dynamic reorganization of the cytoskeleton to promote the formation of axon branches.

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Figure 1: Stages of axon branching in developing CNS pathways.
Figure 2: Cytoskeletal reorganization at different stages of axon branching.
Figure 3: Signalling pathways that promote axon branching.
Figure 4: Competition shapes the morphology of terminal arbors.

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Acknowledgements

We apologize that, owing to space constraints, we could not cite many excellent studies. We thank members of our laboratories for reviewing the manuscript and the helpful comments of the anonymous reviewers. Work from our laboratories is supported by US National Institutes of Health grants NS014428, NS064014 and NS080928.

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  1. Department of Neuroscience and Neuroscience Training Program, 1300 University Avenue, University of Wisconsin-Madison, Madison, 53706, Wisconsin, USA

    Katherine Kalil & Erik W. Dent

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  1. Katherine Kalil
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Correspondence to Katherine Kalil.

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PowerPoint slides

Glossary

Terminal arbors

Highly branched tree-like structures that are found at the ends of axons that innervate target regions.

Collateral branches

Branches that extend from the sides of an axon, often interstitially, and innervate a target by re-branching to form a terminal arbor.

Cytoskeletal dynamics

Cycles of polymerization and depolymerization that result in growth and shrinkage of microtubules and actin filaments, which enable their reorganization.

Filopodia

Finger-like membrane protrusions that contain bundled actin filaments. Filopodia extend transiently from the growth cone, the axon shaft and axon branches.

Neurotrophic factor

A type of molecule, such as brain-derived neurotrophic factor or nerve growth factor, that regulates neuronal growth and survival.

Lamellipodia

Thin sheet-like veils of cytoplasm at the growth cone periphery that are comprised of actin filament networks.

Plus-end-tracking proteins

Plus-end-tracking proteins, such as end-binding protein 1 (EB1) and EB3, associate with the growing plus ends of dynamic microtubules.

RHO GTPases

A family of molecules that regulate cytoskeletal dynamics downstream of guidance cue receptors.

Calcium transients

Transient increases in the level of intracellular calcium that can occur repetitively at different frequencies.

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Kalil, K., Dent, E. Branch management: mechanisms of axon branching in the developing vertebrate CNS. Nat Rev Neurosci 15, 7–18 (2014). https://doi.org/10.1038/nrn3650

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