Despite the importance of myelin for the rapid conduction of action potentials, little is known about the signals that regulate myelin formation. The timing, rate and amount of myelination are controlled by signals from neurons, astrocytes, and some endocrine cells. The recent finding that signals from these same cell types promote the survival of oligodendrocytes has raised the following question: Is myelination primarily regulated by permissive signals, which promote oligodendrocyte survival, or does myelination also require instructive signals, which relate specific steps of the myelination program independently of survival? My hypothesis is that myelination is a default program, which progresses inexorably forward in surviving oligodendrocytes. To test this hypothesis, I will purify and culture oligodendrocytes in the presence of saturating concentrations of oligodendrocyte survival signals. The effect of addition of other cell types on myelination will then be quantified both biochemically and morphologically. Using these procedures, three specific questions will be addressed. (1) Can the amount of myelin produced by an oligodendrocyte in culture be regulated independently of oligodendrocyte survival? (2) Do neurons regulate the amount of axon wrapping by oligodendrocytes independently of oligodendrocyte survival? (3) Do astrocytes regulate the amount of axon wrapping by oligodendrocytes independents of oligodendrocyte survival? If myelination is regulated permissively by oligodendrocyte survival signals, then this would suggest that the number, location and morphology of oligodendrocytes, as well as the timing and amount of myelination could all be the consequence of a simple survival signalling mechanism. Understanding the signalling mechanisms that regulate myelin formation may suggest new ways to enhance remyelination, which is necessary for restoring conduction of action potentials after brain injury and demyelinating disease such as Multiple Sclerosis, an illness which affects 300,000 Americans.
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