Myelination of Neuronal Cell Bodies when Myelin Supply Exceeds Axonal Demand

Abstract

SummaryThe correct targeting of myelin is essential for nervous system formation and function. Oligodendrocytes in the CNS myelinate some axons, but not others, and do not myelinate structures including cell bodies and dendrites [1]. Recent studies indicate that extrinsic signals, such as neuronal activity [2, 3] and cell adhesion molecules [4], can bias myelination toward some axons and away from cell bodies and dendrites, indicating that, in vivo, neuronal and axonal cues regulate myelin targeting. In vitro, however, oligodendrocytes have an intrinsic propensity to myelinate [5, 6, 7] and can promiscuously wrap inert synthetic structures resembling neuronal processes [8, 9] or cell bodies [4]. A current therapeutic goal for the treatment of demyelinating diseases is to greatly promote oligodendrogenesis [10, 11, 12, 13]; thus, it is important to test how accurately extrinsic signals regulate the oligodendrocyte’s intrinsic program of myelination in vivo. Here, we test the hypothesis that neurons regulate myelination with sufficient stringency to always ensure correct targeting. Surprisingly, however, we find that myelin targeting in vivo is not very stringent and that mistargeting occurs readily when oligodendrocyte and myelin supply exceed axonal demand. We find that myelin is mistargeted to neuronal cell bodies in zebrafish mutants with fewer axons and independently in drug-treated zebrafish with increased oligodendrogenesis. Additionally, by increasing myelin production of oligodendrocytes in zebrafish and mice, we find that excess myelin is also inappropriately targeted to cell bodies. Our results suggest that balancing oligodendrocyte-intrinsic programs of myelin supply with axonal demand is essential for correct myelin targeting in vivo and highlight potential liabilities of strongly promoting oligodendrogenesis.

Individual neuronal subtypes control initial myelin sheath growth and stabilization

“…performed similar experiments but used a genetic approach rather than physical ablation to reduce the number of reticulospinal target axons within the posterior spinal cord. In this study oligodendrocytes did not increase myelination of RB sensory axons, but did occasionally perform ectopic myelination of cell bodies [25]. Inverse experiments that increased the target axon supply caused oligodendrocytes to increase myelinating potential in order to meet the increased demand imposed by supernumerary target axons, and ensure the normal rate of myelination for this reticulospinal (Mauthner axon) subtype [38].…”

“…When outcrossed to Tg(nkx2.2a:EGFP-CaaX), which marks oligodendrocyte processes with membrane-tethered EGFP, we observed ensheathment of DsRed + RB axons ( Fig. 1a) [23,25].…”

“…In order to alter target axon availability, we took advantage of the different anatomical positions of [25,30]. We observed reduced average sheath lengths across all spinal cord regions in ablated versus control groups, which could be the result of oligodendrocytes forming more but shorter sheaths on select remaining target axons [25] (Additional Fig. 3e).…”

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

“…Interestingly, other imaging studies have shown that vesicular release is not important for myelin formation on all types of axons even at the same developmental stage (Koudelka et al, ). Separate mechanisms could include axon diameter, axon and oligodendrocyte density, and expression of permissive or inhibitory cell surface cues which may or may not be dependent on neuronal activity or axon molecular identity (Almeida et al, , ; Redmond et al, ; Rosenberg et al, ).…”

“…Other studies have described a role for axonal biophysical properties, such as axon diameter, in regulating myelination and oligodendrocyte wrapping (Friede, ; Goebbels et al, ; Lee et al, ; Mayoral, Etxeberria, Shen, & Chan, ; Rosenberg, Kelland, Tokar, De la Torre, & Chan, ; Voyvodic, ). Moreover, inhibitory or permissive cues expressed by neurons such as Jam2 (Redmond et al, ), ephrin‐A1 (Harboe, Torvund‐Jensen, Kjaer‐Sorensen, & Laursen, ), and Cadm4 (Elazar et al, ) and homeostatic control of oligodendrocyte density (Almeida et al, ) can influence the specificity of oligodendrocyte membrane wrapping to axons and no other neuronal compartments and to some axons and not others. Finally, cell‐intrinsic mechanisms including growth factor sensitivity and electrophysiological properties can impact NG2 glia proliferation, oligodendrocyte generation, and the formation and length of myelin internodes (Bechler, Byrne, & Ffrench‐Constant, ; Hill & Nishiyama, ; Hill, Patel, Medved, Reiss, & Nishiyama, ; Viganò, Möbius, Götz, & Dimou, ).…”