Myelination of correct axons at the right time is critical for overall neural function. During development, all central nervous system (CNS) axons are unmyelinated until oligodendrocytes (OLs) differentiate from their precursor cells (OPCs) and begin to deposit concentric wraps of insulating membrane around most axons to facilitate saltatory conduction of action potentials. Few molecular regulators of OL axon selection are known, but myelination of only appropriate axons may be accomplished by (1) attraction to positive axonal cues, (2) repulsion from inappropriate fibers, or a combination of induction and inhibition. Unexpectedly, our preliminary data suggest a third possibility;that OLs sense and use axon diameter in myelination independent of molecular signaling. OLs cocultured with axon-sized polystyrene nanofibers select only fibers above a threshold diameter to myelinate. Interestingly, the dendrite is geometrically similar to the axon, yet is never myelinated. Thus, we hypothesize that dendrites inhibit their myelination by oligodendrocytes in a contact- dependent manner. To test our hypothesis I will use a novel reductionist coculture system to (1) determine whether dendrites inhibit OL myelination, as well as (2) identify molecular signals localized to dendrite membranes that modulate OL myelination. It is critical to determine how oligodendrocytes interact with, and avoid dendrites to understand normal myelination kinetics and gain insight into dismyelinating diseases.
It is known that inhibitory signaling in the setting of injury or demyelinating disease prevents axon regeneration and myelin repair by oligodendrocytes. Just as the study of axon guidance during development has shed light on strategies to improve neuroregeneration, our studies of inhibition in the setting of normal developmental myelination will likely be relevant to enhancing repair by the removal of inhibitory influences during remyelination.
|Molofsky, Anna V; Kelley, Kevin W; Tsai, Hui-Hsin et al. (2014) Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509:189-94|