Flexible ensheathment of axons enables myelination of complex CNS networks

Nature. 2026 Apr 1. doi: 10.1038/s41586-026-10312-1. Online ahead of print.

ABSTRACT

Myelin sheaths made by oligodendrocytes in the central nervous system (CNS) are critical to circuit function and neural health. The distribution of these insulating sheaths varies substantially between brain regions¹, neuron subtypes² and individual axons^3-5, but the mechanisms that control this patterning are poorly understood. Although previous studies suggested that each oligodendrocyte process generates a single myelin sheath, this mode of axon ensheathment severely constrains myelination along highly branched axons within complex circuits⁶. Here we find that axon ensheathment by individual myelinating processes in zebrafish and mouse proceeds at different rates along axons. This enables a single oligodendrocyte process to extend past axon branch points and nodes of Ranvier before ensheathment, resulting in the formation of chains of myelin sheaths connected by thin cytoplasmic processes. In the cerebral cortex, these 'paranodal bridges' expand the myelin territory produced by individual oligodendrocytes along the highly branched axons of parvalbumin interneurons. Although flexible ensheathment reduces the need for oligodendrocytes, terminal sheaths in myelin chains degenerated more frequently in the aged brain, suggesting that they are more vulnerable to cellular and environmental stress and disproportionally contribute to myelin loss.

PMID:41922759 | DOI:10.1038/s41586-026-10312-1