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

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. To enable the complex neural circuitry found in vertebrates, many axons undergo extensive branching. Here, Kalil and Dent review the roles of extracellular cues, intracellular signalling pathways, cytoskeletal dynamics and neuronal activity in axon branching and terminal arbor formation in the vertebrate CNS. 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