Early myelination involves the dynamic and repetitive ensheathment of axons which resolves through a low and consistent stabilization rate
Abstract
Oligodendrocytes in the central nervous system exhibit significant variability in the number of myelin sheaths that are supported by each cell, ranging from 1-50 (1-8). Myelin production during development is dynamic and involves both sheath formation and loss (3, 9-13). However, how these parameters are balanced to generate this heterogeneity in sheath number has not been thoroughly investigated. To explore this question, we combined extensive time-lapse and longitudinal imaging of oligodendrocytes in the developing zebrafish spinal cord to quantify sheath initiation and loss. Surprisingly, we found that oligodendrocytes repetitively ensheathed the same axons multiple times before any stable sheaths were formed. Importantly, this repetitive ensheathment was independent of neuronal activity. At the level of individual oligodendrocytes, each cell initiated a highly variable number of total ensheathments. However, ~80-90% of these ensheathments always disappeared, an unexpectedly high, but consistent rate of loss. The dynamics of this process indicated rapid membrane turn-over as ensheathments were formed and lost repetitively on each axon. To better understand how these sheath initiation dynamics contribute to the overall stabilization rate we disrupted membrane recycling by expressing a dominant-negative mutant form of Rab5. Oligodendrocytes over-expressing this mutant did not show a change in early sheath initiation dynamics but did lose a higher percentage of ensheathments in the later stabilization phase. Overall, oligodendrocyte sheath number is heterogeneous because each cell repetitively initiates a variable number of total ensheathments that are resolved through a consistent stabilization rate.
Data availability
All datasets generated and analyzed during this study are included in the manuscript.
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Funding
NIH Office of the Director (5F31NS118830)
- Adam Raymond Almeida
NIH Office of the Director (R37NS82203)
- Wendy B Macklin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The Institutional Animal Care and Use Committee at the University of Colorado School of Medicine approved all animal work (#00419). This group follows the U.S. National Research Council's Guide for the Care and Use of Laboratory Animals and the U.S. Public Health Service's Policy on Humane Care and Use of Laboratory Animals.
Copyright
© 2023, Almeida & Macklin
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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