Myelinogenesis
Myelinogenesis is the formation and development of
Stages
Myelin is formed by
The oligodendrocyte lineage can be further classified into four stages based on their relation to the onset of myelination:[6]
- Differentiation: OPCs exit their proliferative, self-renewing state and begin to express genes and proteins associated with oligodendrocyte fate commitment.
- Preoligodendrocyte: These cells express the O4 antigen and develop multiple processes which extend radially with no particular organization.[7]
- Immature oligodendrocyte: Sometimes referred to as premyelinating oligodendrocytes, these cells extend "pioneer processes" which contact axons and anchor premyelinating oligodendrocytes to neurons such that they are poised to commence myelinogenesis in response to axonal signals. These pioneer processes grow longitudinally along their target axons.[7]
- Mature oligodendrocyte: After myelinogenesis, mature oligodendrocytes surround axons in organized, multilamellar myelin sheaths that contain myelin basic protein (MBP) and myelin proteolipid protein (PLP).
Myelinogenesis thus encompasses the process of transition between phases 3 and 4.[6] Upon initiation of myelinogenesis, each pioneer process forms lamellar extensions which extend and elaborate circumferentially around the target axon. This forms the first turn of the myelin sheath.[7] The sheath continues to expand along the length of the target axon while new membrane is synthesized at the leading edge of the inner tongue of the developing myelin sheath, which begins to take on a spiral cross-sectional structure.
To drive proper assembly of membrane layers, PLP is inserted into the membrane to stabilize interactions between external leaflets of the myelin membranes; MBP is locally translated and inserted into the cytoplasmic membrane leaflets to strengthen myelin membranes internally.[8] In concert with the formation of axonal nodes of Ranvier, the myelin sheath's edges form paranodal loops.[9]
Mechanism
The basic helix–loop–helix transcription factor OLIG1 plays an integral role in the process of oligodendrocyte myelinogenesis by regulating expression of myelin-related genes. OLIG1 is necessary in order to initiate myelination by oligodendrocytes in the brain, but is somewhat dispensable in the spinal cord.[10]
Axon-derived signals regulate the onset of myelinogenesis. Researchers studied regenerating PNS axons for 28 weeks in order to investigate whether or not peripheral axons stimulate oligodendrocytes to begin myelination. Experimental induction of myelination by regenerating peripheral axons demonstrated that Schwann cells and oligodendrocytes have a shared mechanism to stimulate myelination.[11] A similar study working to provide evidence for neuronal regulation of myelinogenesis suggested that myelin formation was due to Schwann cells that were controlled by an undefined property of an associated axon.[11]
Recent research in rats has suggested that
Peripheral myelinogenesis
Peripheral myelinogenesis is controlled by the synthesis of proteins P1, P2, and P0.
Myelinogenesis in the optic nerve
The process and mechanistic function of myelinogenesis has traditionally been studied using
One early study showed that in the developing rat optic nerves, formation of
As researchers began to do postnatal research, they found that myelinogenesis in the rat optic nerve initially commences with axons the largest diameters before proceeding to the remaining smaller axons. In the second week postnatal, oligodendrocyte formation slowed – at this point, 15% of axons have been myelinated – however, myelinogenesis continued to rapidly increase. During the fourth week postnatal, nearly 85% of the axons in the rat optic had been myelinated.[14] During the fifth week and onward toward week sixteen, the myelination decelerated and the remaining unmyelinated axons were ensheathed in myelin.[15] Through the rat optic nerve, early research made significant contributions to knowledge in the field of myelinogenesis.
Role of sulfatides
Studies on the developing optic nerve revealed that
The studies on a rat optic nerve revealed that 15 days post-natal is when an increase in myelination is observed. Before this time period, most of the axons, roughly about 70%, are not myelinated. At this time, [35S] Sulfate was incorporated into sulfatide and the activity of cerebroside, sulfotransferase reached a peak in enzyme activity. This time frame also showed a period of maximal myelination based on the biochemical data.[14]
In the CNS, sulfatide, sulfated glycoproteins, and sulfated mucopolysaccharides appear to be associated with neurons rather than myelin. When graphing the amount of sulfatide made from [35S] and the activity of sulfotransferase, we get to distinguished peaks.[14] The peaks occur on the 15th post-natal day. These peaks corresponded with the maximal myelination period of the optic nerve that has been seen throughout the experiment.[14]
In conclusion, the early phase of myelination was correlated with the increases synthesis of lipids, cholesterol, cerebroside, and sulfatide.[14] It is likely that these compounds are synthesized and packaged in the Golgi Apparatus of oligodendroglia.[14] Even though the transport of these lipids is unknown, it appears that myelination is delayed without their synthesis.
Clinical significance
Because
Research History
Another researcher,
The last areas to myelinate are the
In the cerebral convolutions, as in all other parts of the central nervous system, the nerve-fibres do not develop everywhere simultaneously, but step by step in a definite succession, this order of events being particularly maintained in regard to the appearance of the medullary substance. In the convolutions of the cerebrum the investment with medullary substance (myelinisation) has already begun in some places three months before the maturity of the foetus, whilst in other places numerous fibres are devoid of medullary substance even three months after birth. The order of succession in the convolutions is governed by a law identical with the law which I have shown holds good for the spinal cord, the medulla oblongata, and the mesocephalon, and which may be stated somewhat in this way- that, speaking approximately, equally important nerve-fibres are developed simultaneously, but those of dissimilar importance are developed one after another in a succession defined by an imperative law (Fundamental Law of Myelogenesis). The formation of medullary substance is almost completed in certain convolutions at a time when in some it is not even begun and in others has made only slight progress.[19]
References
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: CS1 maint: multiple names: authors list (link - ^ Watkins, T., Mulinyawe, S., Emery, B., Barres, B. (2008). Distinct Stages of Myelination Regulated by Y-Secretase and Astrocytes in a Rapidly Myelinating CNS Coculture System. 555-569
- ^ a b Kinney, H. C., & Volpe, J. J. (2018). Myelination Events. Volpe’s Neurology of the Newborn, 176–188. doi:10.1016/b978-0-323-42876-7.00008-9
- ^ a b c Friedrich, VL., Hardy, RJ., (1996). Progressive Remodeling of the Oligodendrocyte Process Arbor during Myelinogenesis. 243-54.
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: CS1 maint: multiple names: authors list (link - ^ Xin, M. (2005). Myelinogenesis and Axonal Recognition by Oligodendrocytes in Brain Are Uncoupled in Olig1-Null Mice. Journal of Neuroscience, 25(6), 1354-1365. doi:10.1523/jneurosci.3034-04.2005
- ^ a b Weinberg, E., & Spencer, P. (1979). Studies on the control of myelinogenesis. 3. Signaling of oligodendrocyte myelination by regenerating peripheral axons. Brain Research, 162(2), 273-279. doi:10.1016/0006-8993(79)90289-0
- ^ Marziali, L.N., Garcia, C.I., Pasquini, J.M. (2015). Transferrin and thyroid hormone converge in the control of myelinogenesis. Experimental Neurology. Vol 265. 129–141.
- ^ a b c Politis, MJ, N. Sternberger, Kathy Ederle, and Peter S. Spencer. "Studies on the Control of Myelinogenesis." The Journal of Neuroscience 2.9 (1982): 1252-266.
- ^ a b c d e f g h i Tennekoon, GI., Cohen, SR., Price, DL., McKhann, GM. (1977). Myelinogenesis in optic nerve. A morphological, autoradiographic, and biochemical analysis. Journal of Cell Biology, 72(3), 604-616.
- ^ Dangata, Y., Kaufman, M. (1997). Myelinogenesis in the Optic Nerve of (C57BL x CBA) F1 Hybrid Mice: A Morphometric Analysis.European Journal of Morphology, 35(1), 3-18.
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