Elaboration of the myelin sheath involves a precisely ordered sequence of events beginning with the initial ensheathment of the axon, proceeding to formation of multiple loose wrappings and eventually compaction to form the mature multilamellar myelin sheath. These processes imply a temporally regulated program of gene expression in the oligodendrocyte to ensure that the appropriate biochemical components are synthesized in the appropriate proportions at each stage of myelinogenesis. Just before the onset of rapid myelin membrane synthesis the expression of genes of myelin proteins is sharply up-regulated. There is evidence of a coordinated mechanism for synchronous activation of the myelin protein genes. This period of sharp up-regulation of expression of myelin genes is the most vulnerable part of the myelination process and is called the critical period.
Apparently, there are both tissue-specific and stage-specific mechanisms controlling myelin genes. Myelin genes are only expressed in oligodendrocytes and Schwann cells. The expression of the genes is de-
velopmentally regulated and is probably intimately associated with the stage of differentiation of these cells. Control mechanisms are active at the transcrip-tional level. Regulatory regions, including the promoter regions, have been identified for myelin protein genes. Key sites for tissue-specific expression of myelin proteins are clustered near the promoter regions, and within these clusters are several motifs that may be involved in coordinating the regulation of myelin-specific genes. The alternative splicing patterns produced from the primary myelin protein transcripts are also developmentally regulated. The splicing patterns for the different proteins have been shown to change in the course of development.
In both the CNS and the PNS, glial cells are influenced to produce myelin by both neuronal targets that they ensheathe and by a range of hormones and growth factors produced by neurons and astrocytes. There is a continuous oligodendrocyte-neuron-astro-cyte interaction in the process of myelination and myelin maintenance.
Proliferation of oligodendrocyte precursor cells depends on electrical activity of neurons. Oligoden-drocyte number is also dependent on number of axons. Differentiation of oligodendroglia has been shown to depend heavily on the presence and the integrity of axons. Gene expression for myelin constituents is modulated by the presence of axons. Within oligodendrocytes, proteins are produced that are thought to be involved in the induction of myeli-nation (e.g., glia-specific surface receptors for differentiation signals), in the initial deposition of the myelin sheath (e.g., axon-glial adhesion molecules), and in its wrapping and compaction around the nerve axon (e.g., structural proteins of compact myelin). A minimal axonal diameter is important for the initiation of myelination. Final myelin sheath thickness is also related to axonal size. This match is reached by local control mechanisms. Therefore, a single oligo-dendrocyte can be associated with several axons of different sizes, the myelin sheaths being thicker for larger axons. Larger axons also have longer inter-nodes.
Astrocytes are essential in the process of myelina-tion and myelin maintenance. They produce trophic factors, including PDGF,bFGF, IGF-I, and NT-3. These factors promote proliferation, migration and differentiation of oligodendrocyte progenitors, extension of oligodendrocyte processes, adhesion of oligoden-drocyte processes to axons, myelin formation and myelin maintenance.
Hormones have a dramatic effect on myelinogene-sis. A deficiency of growth hormone during the critical period leads to hypomyelination. Most of the effects of growth hormone are mediated by IGF-I. Administration of this substance in early development leads to an increase in all brain constituents, but par ticularly and disproportionately in the amount of myelin produced per oligodendrocyte. Thyroid hormone also has an effect on myelinogenesis. Hypothyroidism during early development leads to hy-pomyelination, whereas hyperthyroidism accelerates myelination. Steroids have a complex influence. None of the myelin protein genes is transcriptionally regulated by steroids,but steroids probably act at the post-translational level, stimulating the translation of MBP and PLP mRNAs and inhibiting the translation of CNP mRNA.
The importance of iron in myelination has been examined. Iron and the iron mobilization protein transferrin are localized in oligodendrocytes, and may participate in the formation and/or maintenance of myelin by complexing with enzymes involved in the synthesis of myelin components.
Myelination is vulnerable to undernourishment. If there is undernourishment during the critical period just prior to the onset of rapid myelin synthesis, myelination is more severely reduced than total brain weight, whereas the number of oligodendrocytes is unaltered. The hypomyelination is permanent. Severe undernutrition during the critical period leads to decreased levels of IGFs and a failure in up-regulation of myelin genes.
Successful myelination is also dependent on function. It is known that myelination is diminished by preventing the conduction of impulses in a nerve. Impulse conduction is a stimulus to myelination. Premature activity accelerates myelination. Hypermyelina-tion has incidentally been noticed in cerebral anomalies, supposedly via the stimulus of epilepsy. It has been shown that oligodendrocyte progenitor cells express adenosine receptors, which are activated in response to action potential firing. Action potential firing leads to the nonsynaptic release of several substances from axons, including ATP and adenosine. Adenosine acts as a potent neuroglial transmitter to inhibit oligodendrocyte progenitor cell proliferation, stimulate differentiation, and promote the formation of myelin.
After formation the myelin sheath and the axon remain mutually dependent. The myelin sheath needs an intact axon, as demonstrated by the studies on wal-lerian degeneration. On the other hand, for maintenance of the normal structure and function the axon requires an intact myelin sheath. Normal astrocytes are essential for an intact myelin-axon unit.
Since myelin, once deposited, is a relatively stable substance metabolically, it is relatively invulnerable to adverse external factors. Generalized vulnerability of myelin to noxious agents and adverse influences is likely to be confined to the period j ust before and during active myelination.
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