Regulation of axonal calibers by myelinating Schwann cells in the peripheral nervous system
Final Report Abstract
Myelin serves as an insulator of neuronal axons that facilitates rapid and precise impulse propagation in the nervous system, a prerequisite for normal motor, sensory, and cognitive capabilities. The velocity of nerve conduction is potently sped up by myelination of axons; on the other hand it is also moderately accelerated by larger axonal diameters. Myelination thus allows rapid impulse propagation with reduced axonal diameters. However, no myelin-dependent mechanism has been reported that restricts the radial growth of axons. By label-free proteomics, STED-microscopy and cryo-immuno electron-microscopy we have identified CMTM6 (chemokine-like factor-like MARVEL-transmembrane domain-containing family member-6) as a myelin protein specifically localized to the Schwann cell membrane exposed to the axon. We find that disruption of Cmtm6-expression in Schwann cells causes a substantial increase of axonal diameters but does not impair myelin biogenesis, radial sorting or the integrity of axons. Increased axonal diameters correlate with accelerated sensory nerve conduction and sensory responses and perturbed motor performance. Both myelination of axons and axonal diameters are frequently impaired in peripheral nerve disorders, but it is not known if the diameters of myelinated axons affect the liability to injury or the efficiency of functional recovery. We thus used mice lacking CMTM6 from Schwann cells as a model of increased diameters of peripheral axons in the presence of appropriate myelination. We subjected Cmtm6-cKo mice to a newly established mild sciatic nerve compression injury that causes temporarily reduced axonal diameters but otherwise comparatively moderate pathology of the axon/myelin-unit. Notably, both of these pathological features were worsened in Cmtm6-cKo compared to genotypecontrol mice early post-injury. The increase of axonal diameters caused by CMTM6-deficiency thus does not override their injury-dependent decrease. Accordingly, we did not detect signs of improved regeneration or functional recovery after nerve compression in Cmtm6-cKo mice; depleting CMTM6 in Schwann cells is thus not a promising strategy toward enhanced recovery after nerve injury. Conversely, the exacerbated axonal damage in Cmtm6-cKo nerves early post-injury coincided with an enhanced immune response and transiently reduced grip strength. Together, this project has thus revealed that Schwann cells restrict the radial growth of axons, thereby optimizing nerve function via a mechanism involving CMTM6. Moreover, our observations support the concept that larger peripheral axons are particularly susceptible toward mechanical trauma.
Publications
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CMTM6 expressed on the adaxonal Schwann cell surface restricts axonal diameters in peripheral nerves. Nature Communications, 11(1).
Eichel, Maria A.; Gargareta, Vasiliki-Ilya; D.’Este, Elisa; Fledrich, Robert; Kungl, Theresa; Buscham, Tobias J.; Lüders, Katja A.; Miracle, Cristina; Jung, Ramona B.; Distler, Ute; Kusch, Kathrin; Möbius, Wiebke; Hülsmann, Swen; Tenzer, Stefan; Nave, Klaus-Armin & Werner, Hauke B.
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Focused ion beam‐scanning electron microscopy links pathological myelin outfoldings to axonal changes in mice lacking Plp1 or Mag. Glia, 71(3), 509-523.
Steyer, Anna M.; Buscham, Tobias J.; Lorenz, Charlotta; Hümmert, Sophie; Eichel‐Vogel, Maria A.; Schadt, Leonie C.; Edgar, Julia M.; Köster, Sarah; Möbius, Wiebke; Nave, Klaus‐Armin & Werner, Hauke B.
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Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5. eLife, 11.
Buscham, Tobias J.; Eichel-Vogel, Maria A.; Steyer, Anna M.; Jahn, Olaf; Strenzke, Nicola; Dardawal, Rakshit; Memhave, Tor R.; Siems, Sophie B.; Müller, Christina; Meschkat, Martin; Sun, Ting; Ruhwedel, Torben; Möbius, Wiebke; Krämer-Albers, Eva-Maria; Boretius, Susann; Nave, Klaus-Armin & Werner, Hauke B.
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Mechanisms of axonal support by oligodendrocyte-derived extracellular vesicles. Nature Reviews Neuroscience, 24(8), 474-486.
Krämer-Albers, Eva-Maria & Werner, Hauke B.
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Myelinated peripheral axons are more vulnerable to mechanical trauma in a model of enlarged axonal diameters. Glia, 72(9), 1572-1589.
Gargareta, Vasiliki‐Ilya; Berghoff, Stefan A.; Krauter, Doris; Hümmert, Sophie; Marshall‐Phelps, Katy L. H.; Möbius, Wiebke; Nave, Klaus‐Armin; Fledrich, Robert; Werner, Hauke B. & Eichel‐Vogel, Maria A.
