CNS Myelin Wrapping Is Driven by Actin Disassembly

Abstract

SUMMARY Myelin is essential in vertebrates for the rapid propagation of action potentials, but the molecular mechanisms driving its formation remain largely unknown. Here we show that the initial stage of process extension and axon ensheathment by oligodendrocytes requires dynamic actin filament assembly by the Arp2/3 complex. Unexpectedly, subsequent myelin wrapping coincides with the upregulation of actin disassembly proteins, rapid disassembly of the oligodendrocyte actin cytoskeleton, and does not require Arp2/3. Inducing loss of actin filaments drives oligodendrocyte membrane spreading and myelin wrapping in vivo, and the actin disassembly factor gelsolin is required for normal wrapping. We show that myelin basic protein, a protein essential for CNS myelin wrapping whose role has been unclear, is required for actin disassembly, and its loss phenocopies loss of actin disassembly proteins. Together these findings provide insight into the molecular mechanism of myelin wrapping and identify it as an actin-independent form of mammalian cell motility.

Oligodendroglia: metabolic supporters of neurons

“…Newly generated myelin layers were found to be deposited by continuous spiraling of the innermost "tongue" of the myelin around the axon, with simultaneous lateral myelin spread along the axonal length (15). This process is dependent on dynamic changes in actin assembly (16,17). One of the main proteins expressed in the myelin, myelin basic protein (MBP), drives myelin actin disassembly and myelin compaction (16,18), whereas another oligodendrocyte protein, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase), counteracts the myelin compaction by promoting actin assembly (19).…”

“…This process is dependent on dynamic changes in actin assembly (16,17). One of the main proteins expressed in the myelin, myelin basic protein (MBP), drives myelin actin disassembly and myelin compaction (16,18), whereas another oligodendrocyte protein, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase), counteracts the myelin compaction by promoting actin assembly (19). Actin assembly allows for uncompacted myelinic channels to develop within the myelin layers, which in turn promotes transfer of small molecules and metabolites between different regions within the oligodendrocyte cytoplasm (see below and ref.…”

Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy

“…Indeed, its periodic character was revealed also in oligodendrocyte precursors (5) and in Schwann cells (6). During axon ensheathment, cytoskeletal rearrangements-and actin disassembly in particular-constitute a fundamental process (10,11). Altogether, these observations raise questions as to the relation and the possible reciprocal influence between the axonal and glial cytoskeletal lattices, especially at paranodes, which are the regions flanking the nodal gaps.…”

Glia in mammalian development and disease

“…Myelination has been studied in earnest for half a century, but the geometry of the wrapping and the cellular (cytoskeletal) mechanisms driving these morphology changes were only recently elucidated (Snaidero and Simons, 2014;Nawaz et al, 2015;Zuchero et al, 2015). Combined with quantitative gene expression data from multiple stages of myelination (Zhang et al, 2014) and numerous gene knockouts affecting myelination, the stage is set to fully unravel the cellular and molecular mechanisms that drive myelination during development, and to understand why remyelination often fails in demyelinating diseases such as multiple sclerosis (MS; Franklin and Goldman, 2015).…”