Abstract
BackgroundMyelination is an exquisite and dynamic example of heterologous cell-cell interaction, which consists of the concentric wrapping of multiple layers of oligodendrocyte membrane around neuronal axons. Understanding the mechanism by which oligodendrocytes ensheath axons may bring us closer to designing strategies to promote remyelination in demyelinating diseases. The main aim of this study was to follow glial-axonal interactions over time both in vitro and ex vivo to visualize the various stages of myelination.Methodology/Principal FindingsWe took two approaches to follow myelination over time: i) time-lapse imaging of mixed CNS myelinating cultures generated from mouse spinal cord to which exogenous GFP-labelled murine cells were added, and ii) ex vivo imaging of the spinal cord of shiverer (Mbp mutant) mice, transplanted with GFP-labelled murine neurospheres. We demonstrate that oligodendrocyte-axonal interactions are dynamic events with continuous retraction and extension of oligodendroglial processes. Using cytoplasmic and membrane-GFP labelled cells to examine different components of the myelin-like sheath, we provide evidence from time-lapse fluorescence microscopy and confocal microscopy that the oligodendrocytes' cytoplasm-filled processes initially spiral around the axon in a corkscrew-like manner. This is followed subsequently by focal expansion of the corkscrew process to form short cuffs, which then extend longitudinally along the axons. We predict from this model that these spiral cuffs must extend over each other first before extending to form internodes of myelin.ConclusionThese experiments show the feasibility of visualizing the dynamics of glial-axonal interaction during myelination over time. Moreover, these approaches complement each other with the in vitro approach allowing visualization of an entire internodal length of myelin and the ex vivo approach validating the in vitro data.
Highlights
Myelination is a fundamental biological process in the developing vertebrate nervous system
These experiments show the feasibility of visualizing the dynamics of glial-axonal interaction during myelination over time
Our studies suggest that the oligodendrocyte process, both during myelination in vitro and after transplantation ex vivo, initially wraps in a corkscrew-like spiral around the axon and that this is followed by a spreading of the membrane to form short cuffs of glial cytoplasm, prior to sheath extension and the formation of internodes of myelin
Summary
Myelination is a fundamental biological process in the developing vertebrate nervous system. The myelin sheath is formed by the spiral wrapping of the oligodendrocyte’s plasma membrane extensions around the axon [1,2]. Myelin sheaths foster rapid and efficient conduction of electrical impulses along axons. The development of the myelin sheath, in which the processes of oligodendrocytes in the central nervous system (CNS) wrap around axons to form multilamellar insulating layers, has allowed for the evolution of highly complex but compact nervous systems [3]. The specialised process of wrapping and compaction of the myelin sheath is not well understood [4]. Myelination is an exquisite and dynamic example of heterologous cell-cell interaction, which consists of the concentric wrapping of multiple layers of oligodendrocyte membrane around neuronal axons. The main aim of this study was to follow glial-axonal interactions over time both in vitro and ex vivo to visualize the various stages of myelination
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