Cytoskeletal control of axon domain assembly and function

•Neuronal polarity and polarized trafficking depends on microtubule specializations.•The axonal cytoskeleton consists of periodic rings of actin, spectrins, and ankyrins.•Nodal ion channels are clustered by a hierarchy of ankyrin/spectrin complexes.•The membrane boundary flanking nodes is the βII spectrin-dependent cytoskeleton.

Neurons are organized and connected into functional circuits by axons that conduct action potentials. Many vertebrate axons are myelinated and further subdivided into excitable domains that include the axon initial segment (AIS) and nodes of Ranvier. Nodes of Ranvier regenerate and propagate action potentials, while AIS regulate action potential initiation and neuronal polarity. Two distinct cytoskeletons control axon structure and function: 1) a submembranous ankyrin/spectrin cytoskeleton that clusters ion channels and provides mechanical support, and 2) a microtubule-based cytoskeleton that controls selective trafficking of dendritic and axonal cargoes. Here, we review recent studies that provide significant additional insight into the cytoskeleton-dependent mechanisms controlling the functional organization of axons.