Architecting the myelin landscape

•Not all axons are myelinated and some axons are discontinuously myelinated.•Oligodendrocytes do not require molecular axonal signals to form myelin membranes.•Axon selection can occur at various stages of oligodendrocyte development.•Axons can express various cues to regulate their selection for myelination.•Synaptic activity and membrane-bound adhesion molecules influence axon selection.

Myelin increases the speed and efficiency of action potential propagation. Yet, not all axons are myelinated and some axons are discontinuously myelinated, prompting the question of how myelinating glia select axons for myelination. Whereas myelination by Schwann cells depends on axonal induction, oligodendrocytes can form myelin membrane in the absence of axons. However, oligodendrocytes alone cannot architect the complex myelination patterns of the central nervous system and recent advances have implicated axonal signaling in this process. This review considers how oligodendrocytes and their precursors could be influenced by inductive, attractive, permissive, repulsive, and preventative cues, and discusses recent evidence identifying synaptic activity and membrane-bound adhesion molecules as such cues directing axon selection.