Mechanisms underlying the CNS myelination: A molecular and morphological analysis of the wrapping process

Abstract

Central nervous system myelin is a multilayered membrane sheath generated by oligodendrocytes for rapid axonal electrical impulse propagation. Both light and electron microscopy have been used to describe morphological features of the myelin sheath. However, the underlying mechanisms of myelin wrapping are still unclear and remain under debate. To investigate the morphology of the CNS myelin sheath during its formation we made use of multiple imaging techniques such as focus ion beam milling coupled to scanning electron microscopy, live imaging, transmission electron microscopy, cryo-immuno labeling and confocal microscopy. With these various approaches we could reconstruct the growing myelin sheath structure in three dimensions and obtain a dynamical view of the myelination. Furthermore, using mouse genetics and virus as reporter we could identify the growth front of the myelin at the inner tongue of the sheath, which is under the control of the PI3K pathway. We identified an elaborated system of cytoplasmic channels within the growing myelin sheath, which serves as tracks for membrane trafficking to the leading edge at the inner most tongue. Most of these channels disappear with the maturation of the sheath but can re-open in the adult when phosphatidylinositol-(3,4,5)-triphosphate was experimentally raised. Taken together, our model suggests that a growing myelin sheath winds around the axon by an advancing inner tongue (underneath the previously deposited membrane) in the center of the myelin segment. Concurrent to this radial growth of the sheath the layers extend laterally towards the node of Ranvier. Our model can explain how myelin is formed as a multilayered structure in the CNS, how abnormal myelin outfoldings are generated in neurological disease and the plasticity of myelin biogenesis in adult life.