Myelination Events

Human Myelinogenesis Is Stage Specific and Initiated Only by the O1 Immature Oligodendroglial Lineage

In the well-studied human optic radiation, cell bodies of immature OLs are present by at least 18 gestational weeks, but the first myelin sheaths are not detected until around 30 weeks. During human parietal white matter development, the percentage of immature OLs in the cerebral white matter remains relatively stable until around 30 weeks, at which time the number of immature oligodendrocytes increases markedly. A number of factors, intrinsic and extrinsic, regulate the further development of oligodendroglia. These factors are discussed later. The onset of myelination of the optic radiation around 30 weeks coincides with the evolution of the visual evoked response between 32 and 35 weeks to the principal waveforms that closely resemble the mature response that is observed by 39 weeks. Consistent with these observations, there is no apparent contact between immature oligodendrocytes and axons before the onset of myelinogenesis ( Fig. 8.2 ). The initiation of myelinogenesis around 30 weeks is preceded by the appearance of a subset of specialized oligodendrocyte processes, pioneer processes that contact and wrap around axons. These initial contact sites serve to anchor the oligodendrocyte before it initiates the spiral wrapping of myelin along the same or other axon segments ( Fig. 8.3 ). In vivo and in vitro approaches support the role of actin filament poly-merization followed by actin disassembly at the leading edge of a myelin sheath to drive sheath protrusion and spreading, respectively.

In the process of myelinogenesis, there is a transitional phase during which the O4O1 premyelin sheath first forms (see Fig. 8.2 ) and then later begins to incorporate MBP. Before active myelination, MBP mRNA is transported in ribonucleoprotein transport granules toward the oligodendrocyte plasma membrane where local translation of MBP and subsequent myelin formation occurs. During the process of MBP mRNA transport, repression of MBP translation is necessary to prevent premature or ectopic myelination. Several mechanisms proposed to regulate translation inhibition during transport include heterogeneous nuclear ribonucleoproteins and small noncoding RNAs.

The premyelination encasement of axons just described contributes to an important MRI correlate, the increase in directionality of water diffusion measured as an increase in relative anisotropy (RA) ( Fig. 8.4 ). In neuroimaging studies of living newborns between 24 and 40 weeks postconception, diffusion tensor MRI (DTI) showed changes in water diffusion that correlate with our morphological data. Thus in central white matter, RA, a measure of preferred directionality of water parallel to fiber tracts, increases markedly from 28 to 40 weeks ( Fig. 8.4 ). This increase in anisotropic diffusion occurred in parallel with a decline in overall water diffusion, as measured by the apparent diffusion coefficient. This combination of findings implies restriction of diffusion perpendicular to fiber tracts and could relate to the ensheathment of fibers by oligodendrocyte processes, as shown in our anatomical studies. Recently, still more sophisticated MRI studies of fetal brain have provided further insights into myelination in the second and third trimesters (see later).

Environmental Interactions Influencing Oligodendrocyte Dynamics

The molecular determinants of the process of myelination include a variety of intrinsic and extrinsic cues. New methodology of single-nuclei RNA sequencing (RNA-seq) reveals transcriptional oligodendrocyte heterogeneity in the human, even among mature oligodendrocytes. Work in zebra fish models indicate that oligodendrocytes are not only distinct in transcriptomic profile but also in function. The development of this heterogeneity likely arises, in part, from microenvironmental interactions or cues that influence the different stages of oligodendroglial development previously discussed (i.e., proliferation, differentiation, and myelination).

During development, neuronal activity regulates axonal selection for myelination such that oligodendrocytes are biased toward active axons for myelination. The mechanisms by which neurons influence oligodendrocyte dynamics include neurotransmitter and neurotrophin interactions with specific receptors expressed on the oligodendrocyte. In addition to neurons, cues from the vasculature and glia (microglia and astrocytes) play an important role in shaping oligodendrocyte development. Vascular endothelial cells secrete Wnt signals that guide migration of oligodendrocytes. During development, microglia secrete insulin-like growth factor–I (IGF-1), which is critical for oligodendrogenesis and myelination. Microglia, under the influence of neuronal activity, phagocytose developing myelin sheaths to ensure correct matching of myelin to neuronal axons during myelination. Astrocytes regulate myelin thickness and nodal gap length via release of thrombin protease inhibitors. Astrocytes also supply external lipids necessary for myelin production. In addition to the factors just listed, other growth factors, hormones, cytokines, surface receptors, and secreted ligands influence oligodendrocyte dynamics. These molecules include basic fibroblast growth factor, nerve growth factor, transferrin, iron, zinc, members of the interleukin-6 family, thyroid hormone, neuregulin, erbB receptors, semaphorins, neuropilin receptors, ephrin, Eph receptors, Nogo, and Nogo receptors. Programmed cell death is an important feature of oligodendroglial development, as it is for neurons (see Chapter 7 ). Data show that approximately 50% of oligodendroglia undergo apoptosis during development.