Mechanotransduction Control of CNS Myelin Sheath Length.

Project Summary Loss and changes to central nervous system (CNS) myelin architecture are prevalent in neurological conditions across the lifespan. Incomplete restoration of myelin sheaths, as seen in multiple sclerosis, leads to disability. Our long-term goal is to identify developmental mechanisms controlling CNS myelin formation essential to CNS function, thus informing future therapies that remediate lost and aberrant myelin in neurological diseases. Myelin sheath architecture, particularly length, controls axonal signaling speed. The >10-fold variation in myelin sheath lengths observed in the CNS adjusts neuronal signaling speeds and, therefore, is thought to enable neural network coordination. Considering this pivotal role for myelin sheath length, a critical question arises: how can appropriate myelin sheath lengths be restored after disruption in neurological disorders to faithfully enable neural networks? The objective of this proposal, to determine mechanisms that establish CNS myelin sheath lengths, is paramount to addressing this question. Contrasting the long-held hypothesis that biochemical instruction from neurons is required for CNS myelination, our team made the unprecedented discovery that diameter of synthetic axons (a.k.a. microfibers) is sufficient to control oligodendrocyte myelin sheath length. These findings led to a new model for myelin formation and to our central hypothesis: axon diameter is a primary instructive cue that establishes CNS myelin length, triggering oligodendrocyte mechanotransduction (i.e., how physical cues are translated into molecular responses) mediating myelin growth. Based upon our preliminary data, we propose that oligodendrocytes respond to the physical cue of diameter (1) via a mechanosensitive ion channel, (2) triggering Ca2+ signaling, and (3) that diameter-triggered mechanotransduction coordinates translational machinery essential to promote myelin sheath growth. We experimentally test this model using complementary approaches: primary oligodendrocyte-microfiber cultures, ex vivo slice cultures, and traditional in vivo tissue analysis. We combine our innovative oligodendrocyte-microfiber cultures with live timelapse imaging and photomanipulation methods that allow us to both observe and manipulate signaling within individual myelin sheaths formed by single oligodendrocytes. This uniquely enables us to assess signals triggered solely by diameter during myelin formation with spatial precision—at the level of individual myelin sheaths–and experimentally interrogate current proposed models for how each myelin sheath independently controls sheath growth/elongation. Identifying mechanotransduction signals that establish myelin sheath length in this proposed project will lay the groundwork to directly test the impact of altered myelin lengths on CNS function that will inform strategies for myelin restoration in neurological disorders.