Architecting the myelin landscape

Abstract

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.

Individual neuronal subtypes control initial myelin sheath growth and stabilization

“…Many neuronal factors influence oligodendrocyte development and myelination, but to date, no single neuronal factor has been identified as necessary to initiate and form myelin sheaths. Although it is possible that such factors will be identified by future studies, an alternative possibility is that oligodendrocytes will initiate wrapping and myelination of any candidate target axon that possesses a supra-threshold axon diameter (> 0.3 µm) and lacks inhibitory signals [17,22], reviewed by [9,13,14]. Our studies do not directly address or exclude this possibility, and it will be important for future studies to determine if the transition from oligodendrocyte-axon contact to initial wrapping is influenced by axonal signals, or is solely mediated by an oligodendrocyte-intrinsic program in vivo.…”

“…For example, emerging evidence indicates that axonal galectins mark non-myelinated axon segments, and that galectins may be mis-expressed within Multiple Sclerosis lesions [43,44]. Numerous additional negative regulators of myelination have been identified that if targeted, could mitigate the barriers to remyelination (reviewed by [9,13,14]). It will be interesting for future studies to identify spinal cord commissural axon properties responsible for the superior sheath stabilizing and growth inducing properties of this subtype in comparison to reticulospinal and spinal sensory axons.…”

“…These complex steps take place over the course of days or weeks, and ultimately are responsible for mature myelin sheaths being positioned at the right location, time, and parameters [7][8][9]. Numerous distinct cell behaviors and specialized mechanisms are deployed during these steps, including dynamic process extension and retraction, cell-type recognition, cell adhesion, and protrusive myelin membrane growth for concentric wrapping and extension along axons (reviewed by [10][11][12]).…”

“…Numerous distinct cell behaviors and specialized mechanisms are deployed during these steps, including dynamic process extension and retraction, cell-type recognition, cell adhesion, and protrusive myelin membrane growth for concentric wrapping and extension along axons (reviewed by [10][11][12]). No single axonal factor has been identified that is required for myelination, but many regulate the abundance, length, and thickness of myelin sheaths [9,[12][13][14][15].…”

Uncovering the biology of myelin with optical imaging of the live brain

“…These cells are tiled and maintain a tightly regulated resident population by balancing self-renewal, apoptosis, and oligodendrocyte differentiation (Barres et al, 1992;Hill, Patel, Goncalves, Grutzendler, & Nishiyama, 2014;Hughes, Kang, Fukaya, & Bergles, 2013;Trapp, Nishiyama, Cheng, & Macklin, 1997). Much is known about the molecular cues that induce oligodendrocyte differentiation from NG2 glia (reviewed in Nishiyama, 2007;Emery, 2010;Liu & Casaccia, 2010;Zuchero & Barres, 2013); however, less is known about the mechanisms inducing myelination of some axons and not others and some axonal segments and not others, in specific patterns at discrete time points (Almeida & Lyons, 2017;Osso & Chan, 2017).…”