National Institute of Neurological Disorders and Stroke 5R01NS135206-03

Mechanotransduction Control of CNS Myelin Sheath Length.

This award funds research to understand how physical cues like axon diameter control the length of CNS myelin sheaths, which is critical for neuronal signaling. The goal is to identify mechanisms of myelin formation to inform therapies for neurological diseases involving myelin loss or disruption.

Description

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. The long-term goal is to identify developmental mechanisms controlling CNS myelin formation essential to CNS function, 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 is thought to enable neural network coordination. A critical question is how to restore appropriate myelin sheath lengths after disruption in neurological disorders. The project hypothesizes that axon diameter is a primary instructive cue that establishes CNS myelin length, triggering oligodendrocyte mechanotransduction, which mediates myelin growth. The study will use primary oligodendrocyte-microfiber cultures, ex vivo slice cultures, and in vivo tissue analysis, employing live imaging and photomanipulation to assess signals triggered by diameter during myelin formation. Identifying mechanotransduction signals that establish myelin sheath length will lay the groundwork for strategies to restore myelin in neurological disorders.

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