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Vertebrate nervous systems rely on rapid nerve impulse transmission to support their complex functions. Fast conduction depends on ensheathment of nerve axons by myelin-forming glia and the clustering of high concentrations of voltage-gated sodium channels (Nav) in the axonal gaps between myelinated segments. These gaps are the nodes of Ranvier. Depolarization of the axonal membrane initiates the action potential responsible for impulse transmission, and the Nav help ensure that this is restricted to nodes. In the central nervous system, the formation of nodes and the clustering of Nav in nodal complexes is achieved when oligodendrocytes extend their processes and ultimately ensheath axons with myelin. However, the mechanistic relationship between myelination and the formation of nodal complexes is unclear. Here we review recent work in the central nervous system that shows that axons, by assembling distinct cytoskeletal interfaces, are not only active participants in oligodendrocyte process migration but are also significant contributors to the mechanisms by which myelination causes Nav clustering. We also discuss how the segregation of membrane protein complexes through their interaction with distinct cytoskeletal complexes may play a wider role in establishing surface domains in axons.