CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes

Since Río-Hortega’s description of oligodendrocyte morphologies nearly a century ago, many studies have observed myelin sheath-length diversity between CNS regions [1–3]. Myelin sheath length directly impacts axonal conduction velocity by influencing the spacing between nodes of Ranvier. Such differences likely affect neural signal coordination and synchronization [4]. What accounts for regional differences in myelin sheath lengths is unknown; are myelin sheath lengths determined solely by axons or do intrinsic properties of different oligodendrocyte precursor cell populations affect length? The prevailing view is that axons provide molecular cues necessary for oligodendrocyte myelination and appropriate sheath lengths. This view is based upon the observation that axon diameters correlate with myelin sheath length [1, 5, 6], as well as reports that PNS axonal neuregulin-1 type III regulates the initiation and properties of Schwann cell myelin sheaths [7, 8]. However, in the CNS, no such instructive molecules have been shown to be required, and increasing in vitro evidence supports an oligodendrocyte-driven, neuron-independent ability to differentiate and form initial sheaths [9–12]. We test this alternative signal-independent hypothesis—that variation in internode lengths reflects regional oligodendrocyte-intrinsic properties. Using microfibers, we find that oligodendrocytes have a remarkable ability to self-regulate the formation of compact, multilamellar myelin and generate sheaths of physiological length. Our results show that oligodendrocytes respond to fiber diameters and that spinal cord oligodendrocytes generate longer sheaths than cortical oligodendrocytes on fibers, co-cultures, and explants, revealing that oligodendrocytes have regional identity and generate different sheath lengths that mirror internodes in vivo. [Display omitted] •Oligodendrocytes, not Schwann cells, form myelin sheaths without axonal signals•Oligodendrocytes sense diameter, increasing sheath length with larger fibers•Oligodendrocytes from cortex and spinal cord form sheaths of different lengths•Regional differences in sheath lengths may initially be hard-wired Much of the mammalian brain comprises axons wrapped by myelin sheaths, whose length determines conduction velocity. Bechler et al. overturn the long-held view that sheath-forming oligodendrocytes are all the same. Oligodendrocytes from different regions generate sheath lengths on microfibers and neurons that reflect thei