Antagonistic Functions of MBP and CNP Establish Cytosolic Channels in CNS Myelin

The myelin sheath is a multilamellar plasma membrane extension of highly specialized glial cells laid down in regularly spaced segments along axons. Recent studies indicate that myelin is metabolically active and capable of communicating with the underlying axon. To be functionally connected to the neuron, oligodendrocytes maintain non-compacted myelin as cytoplasmic nanochannels. Here, we used high-pressure freezing for electron microscopy to study these cytoplasmic regions within myelin close to their native state. We identified 2,′3′-cyclic nucleotide 3′-phosphodiesterase (CNP), an oligodendrocyte-specific protein previously implicated in the maintenance of axonal integrity, as an essential factor in generating and maintaining cytoplasm within the myelin compartment. We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP). Our study provides a molecular and structural framework for understanding how myelin maintains its cytoplasm to function as an active axon-glial unit. [Display omitted] •Characterization of “cytoplasmic channels” in myelin close to their native state•Antagonistic functions of MBP and CNP in generating cytoplasmic channels•CNP interacts with and bundles actin•Reducing MBP levels rescues axonal pathology in CNP-deficient mice Snaidero et al. provide evidence that a system of cytoplasmic-rich channels is generated in myelin sheaths by the antagonist function of MBP and CNP. The authors suggest that these channels are required to provide trophic support to neurons and maintain functional axon-glial units over a long period of time.