Two adhesive systems cooperatively regulate axon ensheathment and myelin growth in the CNS

Central nervous system myelin is a multilayered membrane produced by oligodendrocytes to increase neural processing speed and efficiency, but the molecular mechanisms underlying axonal selection and myelin wrapping are unknown. Here, using combined morphological and molecular analyses in mice and zebrafish, we show that adhesion molecules of the paranodal and the internodal segment work synergistically using overlapping functions to regulate axonal interaction and myelin wrapping. In the absence of these adhesive systems, axonal recognition by myelin is impaired with myelin growing on top of previously myelinated fibers, around neuronal cell bodies and above nodes of Ranvier. In addition, myelin wrapping is disturbed with the leading edge moving away from the axon and in between previously formed layers. These data show how two adhesive systems function together to guide axonal ensheathment and myelin wrapping, and provide a mechanistic understanding of how the spatial organization of myelin is achieved. It remains unclear how myelin is targeted specifically to axons while sparing neuronal cell bodies and dendrites, or how small gaps, the nodes of Ranvier, are left unmyelinated along the axon. In this study, authors used genetic analyses in zebrafish and mice to demonstrate that molecules of the paranodal axo-glial junction act jointly with molecules of the internodal domain to regulate axonal interactions and myelin wrapping, and that in the combined absence of these molecules myelin sheaths are misplaced.