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Myelinogenesis is generally the proliferation of myelin sheaths throughout the nervous system, and specifically the progressive myelination of nerve axon fibers in the central nervous system. This is a non-simultaneous process that occurs primarily postnatally in mammalian species, beginning in the embryo during the midst of early development and finishing after birth.

Function

The myelination process allows neural signals to propagate more swiftly and with less signal loss. This enables better connectivity within specific brain regions and also improves broader neural pathways connecting spatially separate regions required for many sensory, cognitive, and motor functions.

Some scientists consider myelination to be a key human evolutionary advantage, enabling greater processing speeds and leading to further brain specialization. Myelination is considered to be a key developmental stage in the human brain, continuing for at least another 10 to 12 years after birth "before even a general development is completed".[1] Therefore, the rate of development of these brain structures will determine the rate of development of related brain functions.

While the rate at which individual children develop varies, the sequence of development is the same for all children (with a range of ages for specific developmental tasks to take place).

Clinical significance

One disease that has significance that affects Myelinogenesis is Multiple Sclerosis. Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) . There has been tests to find a cure that causes demyelination but there have been none. However, there are possible strategies that may potentially “remyelinate” myelin sheaths in MS.

Myelination is result of a certain type of cell that functions to do this and this is the Oligodendrocytes. “Recent work of this cell has provided needed insight into the process of demyelination, the spontaneous ability of the CNS to regenerate, and the inevitable failure of remyelination” (Rodgers, Robinson, Miller). Focusing on oligodendrocytes to remyelinate made it possible to look at different number of molecular targets that would allow the cells to be protected from being destroyed and allow remyelination. “Combining immunomodulatory therapy with strategies to protect oligodendrocytes from further degeneration and enhance remyelination presents a very real means to improve clinical outcome for chronic progressive patients in the near future” .

In recent research, there are possible ways in treating MS but it will not be cured. The ways that the researchers approached were: 1) halting the pathologic immune response, 2) protecting the CNS from further damage, and 3) repairing the damage through the regeneration of new myelin sheaths, with the overarching goals being to restore conduction and prevent from further axonal loss .

There are drugs that would relieve the symptoms of MS but it will not cure or stop the progression of MS. MS can progressively get worse overtime when untreated. With the approaches, it may be possible to protect oligodendrocytes from degenerating and enhance regeneration with immunotherapies .

Stages

Oligodendrocytes are responsible for the the creation of myelin sheaths. There are “two stages of OL markers, differentiation of OPCs to OLs, and ensheathment of axons…” .

Although the mechanisms and processes of myelination are yet to be fully understood, especially complex gene function, some specific stages in this process have become clear: Stage 1: Axon contact; Stage 2: Glial cell gene production; Stage 3: Axon ensheathment; One of two phases in the early stages of the formation of myelin sheath. “Spiral ensheathment of target axons, begins through the elaboration from each initiator process of lamellar extensions which extend circumferentially around the target axon and thereby form the first turn of its myelin sheath . Stage 4: Maturation.

Many key questions about the myelination process still remain: Why axons of similar size seem to myelinate at the same time; Whether proteins, molecules, and genes are involved in determining axon size; If axonal activity influences the process, if there is a causal relationship, or if there is a more complex combined effect; Why certain processes seem to be lost if myelination does not occur.

Mechanism and process

The principal molecular mechanisms that control the process of myelinogenesis are not well known. Numerous studies have primarily focused on elucidating the underlying neuronal control of myelinogenesis; such studies have provided several possibilities.

One such study focused on the signaling of oligodendrocyte myelination by regenerating peripheral axons. 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 between Schwann cells and oligodendrocytes there must be shared mechanism to stimulate myelination . A similar study working to provide evidence for neuronal regulation of myelinogenesis suggested that myelin formation due to Schwann cells are controlled by an undefined property of the associated axon .

Another such study in mice determined that the helix-loop-helix transcription factor, OLIG1, plays an integral role in the process of oligodendrocyte myelinogenesis. OLIG1 controls regulation in several myelin related genes, while suppressing others. On a cellular level, the study experimentally demonstrated that OLIG1 is necessary in order to stimulate myelination by oligodendrocytes in the brain. However, spinal cord related oligodendrocytes demonstrated significantly less need for OLIG1 regulation in order to begin myelination .

Related research

Kept from previous author

Another researcher, Paul Flechsig spent most of his career studying and publishing the details of the process in the cerebral cortex of humans. This takes place mostly between two months before and after birth. He identified 45 separate cortical areas and, in fact, mapped the cerebral cortex by the myelination pattern. The first cortical region to myelinate is in the motor cortex (part of Brodmann's area 4), the second is the olfactory cortexand the third is part of the somatosensory cortex (BA 3,1,2). The last areas to myelinate are the anterior cingulate cortex (F#43), the inferior temporal cortex (F#44) and the dorsolateral prefrontal cortex (F#45).

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.[2]

Myelinogenesis in the optic nerve

The process and mechanistic function of myelinogenesis has been studied using ultrastructure and biochemical techniques in rat optic nerves. The implementation of this method of study has allowed for experimental observation of myelinogenesis in a model organism nerve that consists entirely of unmyelinated axons. Further, the use of the rat optic nerve provides insight into improper and atypical courses of myelinogenesis .

In the developing rat optic nerves, formation of oligodendrocytes and subsequent myelination occurs postnatal. In the optic nerve, oligodendrocyte cells divide for the final time at five days, with the onset of myelin formation occurring on or around day 6 or 7. However, the exact process by which the oligodendrocytes are stimulated to produce myelin is not yet fully understood. Although, early myelination in the optic nerve has been linked to a rise in the production of various lipids – cholesterol, cerebroside, and sulfatide .

Initially, myelinogenesis in the rat optic nerve commences with the largest diameter axons before much proceeding to the remaining smaller axons. In the second week postnatal, oligodendrocyte formation slows – at this point, 15% of axons have been myelinated – however, myelinogenesis continues to rapidly increase. During the fourth week postnatal, nearly 85% of the axons in the rat optic have been myelinated . During the fifth week and onward toward week sixteen, the myelination decelerates and the remaining unmyelinated axons are ensheathed in myelin .

Importance of sulfate

Studies on the developing optic nerve revealed that galactocerebroside (which forms sulfatide) appeared on the 9th post-natal day and reached a peak on the 15th post-natal day . This expression was similar to a period where the optic nerve showed a maximal myelination period of the axon. As the activity of axon myelination decreased, and one could conclude that the activity of the enzyme is paralleled with the incorporation of [35S] into sulfatide in vivo.

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 .

In the Central Nervous System, 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 . 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 .

In conclusion, the early phase of myelination was correlated with the increases synthesis of lipids, cholesterol, cerebroside, and sulfatide . It is likely that these compounds are synthesized and packaged in the Golgi Apparatus of oligodendroglia . Even though the transport of these lipids is unknown, it appears that myelination is delayed without their synthesis.

Studies on the control of myelinogenesis

Myelinogenesis is controlled by the synthesis of proteins P1, P2, and P0 . By using SDS-PAGE revealed distinct bands with band sizes of 27,000 Daltons (P1), 19,000 Daltons (P2), and 14,000 Daltons (P0). Studies have also shown that P1 and P2 are active before Po since this protein is comes from the peripheral nervous system . In the process of regeneration, Schwann cells re-synthesize proteins associated with myelin-specific proteins when axonal presence is re-established. A key part of the experiment was to indicate that Schwann cells don't synthesize myelin-proteins in the absence of axons in vivo. Synthesis of detectable myelin-specific proteins do not occur in Schwann cells free of axons and thus proving that the axons instruct the Schwann cells to initiate the production of myelin proteins immediately after establishment of axonal association .

Even though the axon completely controlled the synthesis of these proteins, the axon alone isn’t enough for myelination. As the experiment progressed, it became more evident that membrane-membrane interactions between axons somehow promoted the synthesis of the P1, P2, and P0 proteins. It is likely that axons from myelinated fibers are able to induce Schwann cell myelin protein synthesis throughout the adult life, but this is something that could be researched further.

References

BUTT, A. M., IBRAHIM, M. and BERRY, M. BUTT, A., IBRAHIM, M., & BERRY, M. (1997). Journal Of Neurocytology, 26(5), 327-338. doi:10.1023/a:1018556702353

Butt, A., & Berry, M. (2000). Oligodendrocytes and the control of myelination in vivo: new insights from the rat anterior medullary velum. Journal Of Neuroscience Research, 59(4), 477-488.

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.

Eilam, R., Bar-Lev, D., Levin-Zaidman, S., Tsoory, M., & LoPresti, P. et al. (2014). Oligodendrogenesis and myelinogenesis during postnatal development effect of glatiramer acetate. Glia, 62(4), 649-665. doi:10.1002/glia.22632

Flechsig, Paul (1901-10-19). "Developmental (myelogenetic) localisation of the cerebral cortex in the human subject". The Lancet: 1028.

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.

Tennekoon, GI., Cohen, SR., Price, DL., McKhann, GM. (1977). Myelinogenesis in optic nerve. A morphological, autoradiographic, and biochemical analysis. The Journal Of Cell Biology, 72(3), 604-616.

Weinberg, H., & Spencer, P. (1976). Studies on the control of myelinogenesis. II. Evidence for neuronal regulation of myelin production. Brain Research, 113(2), 363-378. doi:10.1016/0006-8993(76)90947-1

Weinberg, E., & Spencer, P. (1979). Studies on the control of myelinogenesis. 3. Signalling of oligodendrocyte myelination by regenerating peripheral axons. Brain Research, 162(2), 273-279. doi:10.1016/0006-8993(79)90289-0

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.

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

http://onlinelibrary.wiley.com/doi/10.1002/glia.22632/abstract

http://cogweb.ucla.edu/CogSci/Myelinate.html