Myelination

UELI SUTER , RUDOLF MARTINI , in Peripheral Neuropathy (Fourth Edition), 2005

Regulation of Myelin Genes

Myelination during development and after demyelination demands an extremely high synthesis rate of myelin proteins and lipids within a short period of time. To accomplish this precisely regulated task, the myelination process is guided by the coordinated expression of genes that encode myelin components. 185 The principal control of the system is governed by transcription factors. Some of these are present ubiquitously in many cell types, including Schwann cells, whereas others are more specifically expressed. Together, these factors are responsible for the cell type–specific and differentiation stage–specific gene expression, including the regulation of myelination. 197 In addition to the pivotal roles of transcription factors in orchestrating the myelination process, additional regulation at the posttranscriptional level by altering mRNA stability is likely, but this possibility has not yet been thoroughly explored experimentally in the PNS. Recent evidence suggests a particularly important role for the close interaction between neurons (axons) and the ensheathing Schwann cells in the regulatory network governing myelination. 104, 157 This finding may be part of the reason why the use of transcription factors by Schwann cells is quite different from that by oligodendrocytes, the myelinating counterpart in the CNS. 197

Several parallel strategies have been employed to examine myelin gene regulation in the PNS. Major efforts have focused on the identification of transcription factors expressed by Schwann cells that might be master regulators of myelin gene expression, as has been found during muscle development (MyoD). 20 This hunt has proved to be difficult, but some candidates have been identified. In particular, suppressed cyclic AMP (cAMP)–inducible POU protein (SCIP, Tst-1, Oct-6) plays a critical role in the regulation of PNS myelination because SCIP-deficient mice are characterized by severe congenital hypomyelination of peripheral nerves. However, the defect is transient and the nerves are close to normal at 3 months of age. 81 Similarly, the zinc-finger family protein Egr2 (Krox20) appears to be required for the normal development of the myelinating Schwann cell phenotype. Transgenic mice carrying a null mutation in the egr2 gene display severe defects in Schwann cell development resulting in hyperproliferation and presumed differentiation arrest at the premyelination stage. 186 Egr2 also regulates the expression of genes involved in PNS myelination. 119 In line with these findings, different mutations affecting Egr2 are associated with CMT disease type 1, the Déjèrine-Sottas syndrome, and congenital hypomyelinating neuropathy (see Chapter 72). 119, 194

Additional transcription factors that may affect late steps in the differentiation of Schwann cells include Pax3, Krox24, and Brn5. 157, 199 Of particular importance is the transcription factor Sox10, which has been identified as a common transcriptional modulator for SCIP, Krox20, and Pax3. It was suggested that Sox10 is responsible for cell-type specificity by interacting with these transcription factors in developing and mature glia. 87 Furthermore, a crucial role of Sox10 in early Schwann cell development has been demonstrated 23, 126 and reviewed by Lobsiger and colleagues. 100 With regard to PNS myelination, Sox10 regulates MPZ (P0) and GJB1 (Cx32) gene expression. 19, 132 Mutations in each of these genes are responsible for distinct forms of CMT disease (see Chapter 71). Sox10 mutations are associated with Shah-Wardenburg syndrome (WS4), a neurocristopathy with intestinal aganglionosis, pigmentation defects, sensorineural deafness, and, in specific cases, alterations in myelination in the PNS and CNS. 80, 125, 138 These Sox10 mutants are unable to activate the Cx32 promoter and, conversely, a specific mutation in the Cx32 promoter, previously described in a patient with CMT disease, impairs Sox10 function directly. 19 This elegant series of studies provides a direct genetic link between the regulation of myelin gene expression by the transcription factors Egr2 and Sox10 and myelin deficiencies in inherited peripheral neuropathies. It suggests that factors involved in the regulation of myelin gene expression should be generally considered as candidates involved in the etiology of peripheral neuropathies. Furthermore, a general concept emerges that correct myelination, myelin maintenance, and axonal maintenance are crucially dependent on the correct expression levels of myelin proteins. 13, 104

Besides studying the role of transcription factors and their modulators, myelination-related, cell type–specific control can also be elucidated by the identification and characterization of cis-acting control elements of genes encoding myelin components. 196 Transfection experiments in cultured Schwann cells have been used as a standard assay in this regard, followed by classic footprinting and bandshift assays to identify the sequences that are bound by transcription factors. 24 However, there are limitations with this assay system because Schwann cells that have been kept in culture do not express myelin genes up to the rates that are observed in vivo during development and in regeneration. Co-culturing with neurons is required for myelination, but because of technical restrictions, this system is not well suited for gene transfer analysis. Transgenic mice, however, provide an excellent assay system to examine myelin gene regulation because numerous developmental and physiologic signals for correct interactions are present. Such a strategy has recently led to the identification of Schwann cell–specific enhancers that mediate axonal regulation in SCIP, 106 MBP, 59 Egr2, 69 and PMP22 103 genes. Initial results of studies with similar aims have been reported for the 2′,3′-cyclic nucleotide 3′-phosphodiesterase gene, 30, 73 the P0 gene, 52 and the proteolipid protein gene. 105 Apart from providing important insights into the molecular basis of the regulation of myelin genes, these studies have also generated important tools to target transgenic expression of genes of choice to Schwann cells. 53, 143 PMP22, the dosage-sensitive culprit gene of CMT disease type 1A and hereditary neuropathy with liability to pressure palsies, was reviewed by Suter and Snipes. 176 Studies on PMP22 gene regulation during myelination may also provide the basis for future therapies. 77, 207

What are the signal transduction events that regulate Schwann cell myelination, and by which transcriptional effectors? Examination of the role of different signaling pathways in Schwann cell differentiation using Schwann cell–neuron co-cultures revealed that, at early stages, inhibition of phosphatidylinositol 3 (PI3)-kinase, but not myelin-associated protein (MAP) kinase, blocked Schwann cell elongation and subsequent myelination. 113 After Schwann cells established a one-to-one relationship with axon segments, inhibition of PI3-kinase did not block myelin formation, but the myelin segments were shorter and the rate of myelin protein accumulation was decreased. PI3-kinase inhibition had no detectable effect on the maintenance of myelin sheaths in mature myelinated co-cultures. Interestingly, glial growth factor (GGF), a neuregulin-1 isoform, significantly inhibited myelination in the same system by preventing axonal segregation and ensheathment. 208 Treatment of established myelinated cultures with GGF resulted in striking demyelination. The neuregulin receptors ErbB2 and ErbB3 are expressed on ensheathing and myelinating Schwann cells and are rapidly activated by GGF treatment. GGF treatment of myelinating cultures also induced phosphorylation of PI3-kinase, MAP kinase, and a 120-kDa protein. Thus neuronal mitogens, including neuregulins, may inhibit myelination during development, and activation of mitogen signaling pathways may contribute to the initial demyelination and subsequent Schwann cell proliferation observed in various pathologic conditions.

Surprisingly, functional information about the downstream transcriptional effectors mediating the events described above is still scarce. 196 Several AP-1 (dimeric transcription factors of the Jun, Fos, and ATF family of basic leucine zipper proteins) binding sites have been found in putative regulatory regions of myelin genes. However, although c-Jun is expressed by Schwann cells, a direct functional role of AP-1 transcription factors in regulating PNS myelination remains unclear. 174 Similarly, the transcription factor CREB (which becomes activated through phosphorylation) is found in Schwann cells, and a protein kinase A–dependent increase of CREB phosphorylation was observed after axonal stimulation and the elevation of cAMP, intracellular calcium, platelet-derived growth factor, or endothelins. Furthermore, β-neuregulin treatment causes sustained CREB phosphorylation, and this effect appears to be mainly dependent on the MAP kinase pathway. 179 Although this is strong evidence for a function of CREB in the regulation of Schwann cells, a direct link to myelination has not yet been described. Such a link has been established for progesterone that promotes the myelination of sciatic nerves during regeneration after a cryolesion. 86 Progesterone triggers a strong upregulation of Egr1 (Krox24), Egr2, Egr3, and FosB in cultured Schwann cells, most likely at the transcriptional level via the interaction of the hormone with its cognate receptor. Furthermore, neuroactive steroids are able to upregulate the mRNA levels of PMP22 and P0 and, thus, specific receptor ligands or antagonists may be promising candidates for therapeutic approaches in demyelinating inherited neuropathies. 101, 166

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Nervous System, Neuroembryology of

H.B Sarnat , L. Flores-Sarnat , in Encyclopedia of the Neurological Sciences (Second Edition), 2014

Myelination

Myelination of axons is not absolutely required for neuronal function, and many axons normally remain unmyelinated throughout life. Examples are many autonomic, especially sympathetic, nerves and more than half of the axons of the corpus callosum. Nevertheless, myelination greatly increases speed of conduction, and synaptic blocks may result from inadequate myelination. Myelin sheaths of axons are produced by oligodendrocytes, specialized glial cells derived from the neuroepithelium, in the CNS and by Schwann cells, derived from neural crest, in the peripheral nervous system (PNS). The transition from oligodendrocytes to Schwann cells forming continuous myelin sheaths can be seen at spinal and cranial nerve roots.

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Epilepsy

Gregory L. Holmes , ... Olivier Dulac , in Handbook of Clinical Neurology, 2012

Developmental changes in myelination

Myelination is an important developmental process that begins during the fifth fetal month with myelination of the cranial nerves, and continues throughout life. The major changes in myelination occur from 3  weeks to 1   year for all brain regions. Myelination appears to occur earliest in the posterior fossa, with the middle cerebellar peduncle identifiable by age 3   months. By the age of 1   year, all major white matter tracts including the corpus callosum, subcortical white matter, and the internal capsule are well defined. In contrast to the high rate of myelination in the first year, the changes between 1 and 2   years are more subtle, although changes in radial diffusivity on diffusion tensor imaging suggest a pruning process. The development of white matter begins from the center to the periphery and from the occipital to the frontal lobes (Gao et al., 2009).

During the first year of life, the magnetic resonance imaging (MRI) white matter signal on T2 changes from hyperintense to hypointense, and vice versa on T1 (Barkovich, 2000). Like other membranes, myelin is composed of a bilayer of lipids with several large proteins, most of which span the bilayer (including myelin basic protein and proteolipid protein). The outer lipid layers are composed mainly of cholesterol and glycolipids, whereas the inner portion of the lipid bilayer is composed mainly of phospholipids. It is thought that the high signal intensity seen on T1-weighted images with the maturation of white matter results from T1 shortening caused by the cholesterol, glycolipids, and possibly the proteins in the outer lipid layers of the membrane, whereas it is thought that the diminishing signal intensity seen on the T2-weighted images with maturation results from a decreased number of water molecules caused by development of the hydrophobic phospholipid inner layer (Svennerholm and Vanier, 1978; Svennerholm et al., 1978; Holland et al., 1986; Barkovich et al., 1988).

The changes in signal intensity in myelin with age may make interpretation of MRI scans in children with epilepsy difficult. Distinguishing leukoencephalopathies from normal age-dependent changes in myelination can be challenging. In addition, how well cortical dysplasias are seen on the MRI may be related to the degree of myelination. In some cortical dysplasias the lesion may be seen better on MRI before extensive myelination occurs (Eltze et al., 2005). However, in some cases cortical dysplasias may be more evident with increased myelination (Yoshida et al., 2008).

In addition to myelination affecting the clinical and EEG features of seizures, epilepsy and its causes may alter myelination. For example, delays in myelination have been seen in children with infantile spasms (Muroi et al., 1996; Natsume et al., 1996; Takano et al., 2007). Children with prenatally or perinatally acquired brain lesions appear to have more severe delays of myelination (Schropp et al., 1994). The mechanism by which seizures alter the rate of myelination is not known.

The myelination pattern may also have a significant role in when infantile spasms begin. Koo et al. (1993) reviewed 93 cases of infantile spasms with focal cerebral lesions confined to frontal, centrotemporoparietal, or occipital regions. The mean age of onset of infantile spasms was around 3   months in patients with occipital lesions, versus 6   months in those with centrotemporoparietal lesions, and 10   months in those with frontal lesions. It is therefore of considerable interest that myelination occurs in the occipital lobe and moves forward into the temporal, parietal, and frontal lobes. The age distribution pattern of spasm onset according to localization of cortical lesion was therefore closely correlated with that of the normal sequence of brain maturation, suggesting that myelination may be necessary for the seizures to occur.

With greater myelination of the frontal lobes there is a greater likelihood of seeing spike–wave discharges arising frontally. Lennox–Gastaut syndrome, with frontal predominantly slow spike–wave discharges, typically does not begin in the first year of life but may evolve from West syndrome as the brain myelinates more fully. Likewise, the development of epilepsy with myoclonic–astatic seizures is an age-related phenomenon, occurring in toddlers but not in infants (Doose, 1992).

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Neurons and Their Properties

David L. Felten MD, PhD , ... Mary Summo Maida PhD , in Netter's Atlas of Neuroscience (Third Edition), 2016

1.16 Development of Myelination and Axon Ensheathment

Myelination requires a cooperative interaction between the neuron and its myelinating support cell. Unmyelinated peripheral axons are invested with a single layer of Schwann cell cytoplasm. When a peripheral axon at least 1 to 2 µm in diameter triggers myelination, a Schwann cell wraps many layers of tightly packed cell membrane around a single segment of that axon. In the CNS, an oligodendroglia cell extends several arms of cytoplasm, which then wrap multiple layers of tightly packed membrane around a single segment of each of several axons (or occasionally two autonomic preganglionic axons). Although myelination is a process that occurs most intensely during development, Schwann cells may remyelinate peripheral axons following injury, and oligodendroglial cells may proliferate and remyelinate injured or demyelinated central axons in diseases such as multiple sclerosis.

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Structural Brain Development

J.B. Colby , ... E.R. Sowell , in Neural Circuit Development and Function in the Brain, 2013

12.2.3 Myelination

Myelination of axonal projections by oligodendroglia is also a prominent component of early brain development. This process begins in utero, continues rapidly through the first 5 years of life, and remarkably extends – although at a slower rate – through young adulthood. Intracortical histological preparations by Kaes in 1907 were some of the first to demonstrate this prolonged trajectory of myelination, along with its striking regional variability in timing (Kaes, 1907; Kemper, 1994). His work not only demonstrated earlier trajectories in some areas (posterior temporal, precentral, and postcentral cortex) than others (superior parietal, anterior temporal, and anterior frontal cortex), but also showed that regions with a more protracted developmental trajectory have more pronounced changes during older age. This has helped to form the 'first-in-last-out' theory of aging (Davis et al., 2009), which suggests that higher-order cognitive manifestations (e.g., problem solving and logical reasoning) – some of the last to develop (Luna et al., 2004) – are some of the first to degenerate in old age. Furthermore, the visible spread of myelin outwards into the cortex results in an apparent cortical thinning, which suggests that normal developmental decreases in cortical thickness (discussed in Section 12.4.3) may be due, in part, to this progressive increase in myelin and not simply to regressive changes like synaptic pruning and cell loss (see Rubenstein and Rakic, 2013).

These initial observations in intracortical tissue were extended to the white matter in the pioneering work performed by Yakovlev and Lecours in the 1960s. They demonstrated that white matter myelination begins in utero during the second trimester of pregnancy and continues throughout young adulthood (Yakovlev and Lecours, 1967). Additionally, they extended the earlier observations of regional variations in the timing of myelination and described a general posterior-to-anterior trend in the timing of white matter myelination during development that has also been replicated in other samples (Kinney, 1988). Later independent research, targeting the hippocampal formation, has also noted striking increases in myelination, with a 95% increase observed in the extent of myelination relative to brain weight during the first two decades of life. Surprisingly, the authors noted that expanding myelination continued even through the fourth to sixth decades of life (Benes et al., 1994). Taken together, these observations suggest that structural white matter development, in the form of advancing myelination, proceeds in tune with overall cognitive development – with areas involved in lower-order sensory and motor function myelinating earlier than areas involved with higher-order executive function. This correlated timing implies there may be some relationship between advancing brain function and increased myelination; however, postmortem studies are limited from investigating this directly.

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Essays on Developmental Biology, Part A

Carmen Birchmeier , David L.H. Bennett , in Current Topics in Developmental Biology, 2016

3 Entry into the Myelination Program

Myelination is essential for neuronal function, and deficits in myelination cause devastating disease ( Nave & Trapp, 2008; Quarles, Macklin, & Morell, 2006; Suter & Scherer, 2003). Myelin electrically insulates axons and allows fast propagation of nerve impulses by saltatory conduction. The overall conduction velocity of the myelinated axon is determined by myelin and axonal thickness, internodal length, and myelin integrity (Court et al., 2004; Waxman, 1980). The overall organization of the myelin sheath is similar in the PNS and CNS, but substantial differences exist in development, assembly, and molecular composition of the myelin, or in the extrinsic signals and transcription factors that drive myelination (Brinkmann et al., 2008; Emery, 2013; Hornig et al., 2013; Quarles et al., 2006). We discuss here the molecular processes active during peripheral myelination.

Myelination is tightly controlled by axons. Only medium and large diameter axons are myelinated, and thin axons (smaller than 1   μm) are ensheathed by nonmyelinating Schwann cells and are organized in bundles (called Remak bundles; Hillarp & Olivecrona, 1946). Thin and thick myelinated axons have thin and thick myelin sheaths, respectively. This leads to the constant G-ratio (defined as ratio of axonal diameter to diameter of the myelinated fiber) of 0.67 (Donaldson & Hoke, 1905). Thus, the axon provides cues that determine its myelination fate and the thickness of its myelin sheath. Conversely, Schwann cell-derived signals allow neuronal survival by providing trophic signals and/or metabolic support (Riethmacher et al., 1997; Viader et al., 2013). Interactions between Schwann cells and axons also guide cell adhesion molecules and ion channels into distinct axonal domains, the nodes of Ranvier and internodes, a prerequisite for efficient saltatory conduction (Eshed-Eisenbach & Peles, 2013). Finally, intact myelin provides signals for radial axonal growth and enhances axonal transport, which is impaired in demyelinating diseases (de Waegh, Lee, & Brady, 1992; Kiryu-Seo, Ohno, Kidd, Komuro, & Trapp, 2010; Saxton & Hollenbeck, 2012; Watson, Nachtman, Kuncl, & Griffin, 1994).

The surface membrane of Schwann cells was estimated to increase during myelination up to several thousand-fold. Therefore, myelination is accompanied by the production of huge amounts of myelin proteins and lipids. The entry into the myelination program in Schwann cells is controlled on the transcriptional level by factors like Egr2 (Krox-20), Pou3f1 (Oct-6/Scip/Tst-1), and Pou3f2 (Brn2) that interact with Sox10 to drive expression of myelin genes (Bermingham et al., 1996; Finzsch et al., 2010; Jaegle et al., 2003; Topilko et al., 1994; see also Svaren & Meijer, 2008, and the references herein). In addition, lipid biosynthesis genes are coordinately regulated, and the Srebp/Scap transcription factors and the control of their expression play important roles in lipid production (Verheijen et al., 2009; Norrmen et al., 2014). Extrinsic signals that trigger entry into myelination are provided by Nrg1/ErbB2/3, GPR126, integrins, extracellular matrix components, and ADAM22/Lgi4 (Bermingham et al., 2006; Nave & Salzer, 2006; Ozkaynak et al., 2010; Raphael & Talbot, 2011; Taveggia, Feltri, & Wrabetz, 2010). Thus, the Nrg1/ErbB2/3 system that regulates expansion of the progenitor pool and migration in early Schwann cell development is unexpectedly reused for myelination. It was therefore discussed whether Nrg1 provides instructive or permissive signals during myelination (Lemke, 2006; Nave & Salzer, 2006).

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Oligodendrocyte Responses, Myelination, and Opioid Addiction Treatments

Carmen Sato-Bigbee , Susan E. Robinson , in Neuropathology of Drug Addictions and Substance Misuse, 2016

Applications to Other Addictions and Substance Abuse

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Defects in myelination and myelin structure have also been observed in adult individuals exposed to cocaine, cannabinoids, alcohol, and methamphetamines.

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Perinatal exposure to cocaine has been associated to delayed glial development and brain myelination.

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Altered glial development and delayed myelination were also observed in fetal alcohol syndrome.

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Imaging studies also suggested decreased myelination in the brain of children exposed in utero to methamphetamines.

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Studies in rodents suggested that activation of cannabinoid receptors in the developing brain may accelerate myelination.

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White matter density changes have been reported in adolescents using cannabinoids although the variability and restricted number of studied individuals preclude clear conclusions on the effects of these drugs on developmental myelination.

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Schwann Cells and Axon Relationship

R.D. Fields , in Encyclopedia of Neuroscience, 2009

Myelination

Myelination begins after Schwann cells exit the cell cycle. In the promyelinating stage, just before beginning to form myelin, Schwann cells begin to increase expression of several myelin proteins, including myelin-associated glycoprotein (MAG) and myelin protein zero. The latter is the most abundant protein in peripheral nerve, and it is responsible for maintaining the compact layers of myelin together. A different protein, proteolipid protein, performs this function in central nervous system myelin.

The process of myelination begins by a Schwann cell first engulfing several axon segments at once ( Figure 1(a) ). These are sorted out until the cell selects only one axon segment to wrap with myelin ( Figure 1(b) ). Formation of extracellular matrix is an essential early step in the process, and in cell culture, myelination will not commence until ascorbic acid is added to the medium to promote formation of the basal lamina ( Figure 1 , black arrows). Laminin-2 is a major component of basement membrane, and mutations in α 2 laminin cause dysmyelination. β 1 integrin is one of the laminin receptors on Schwann cells, and animals lacking this receptor fail to establish the one-to-one relation with axons. Dystroglycan, another laminin receptor on Schwann cells, is not vital for early stages of myelination, but it participates in organizing the Schwann cell structure at the node.

Figure 1. Schwann cell–axon relations during remyelination of regenerated axons in rat sciatic nerve. After axotomy, Schwann cells (SC) provide trophic factors and extracellular matrix components (ECM) to guide regenerating axons to form appropriate connections. (a) Early events in remyelination by SCs can be seen in sciatic nerve regenerating after being severed. Cellular processes extending from SCs (white arrows) sort out unmyelinated axons (ax) from larger diameter axons (AX). The small-diameter axons will become engulfed together in bundles inside nonmyelinating SCs and remain unmyelinated. A single SC will become associated with one segment of a large-diameter axon and begin synthesizing multiple layers of myelin membrane around a segment of the axon (M). This will provide rapid, saltatory impulse conduction by insulating the axon and organizing the fiber into internodal and nodal domains having distinct types of ion channels. Basal lamina, synthesized by SCs (double black arrows), is necessary for sorting out large-diameter axons and initiating myelination. (b) A large-diameter axon in the earliest stages of myelination is shown ensheathed by a single wrap of SC membrane. (c) Another myelinated axon shows a later stage in which compact myelin is formed by wrapping multiple layers of membrane around the axon and squeezing the cytoplasm out from between the stacks of insulating membrane. Scale bar   =   500   nm.

The factors initiating myelination are not fully understood, nor is it clear why Schwann cells only myelinate large-diameter axons. Just before Schwann cells begin to myelinate, nuclear factor-kappa B (NF-κB) is upregulated, and its activation and translocation to the nucleus is necessary to regulate transcription of genes essential for myelination. A number of transcription factors are involved in initiating myelination, including Krox20/EGR2, NGFI-1-binding proteins, Oct6, and BRN2. As might be expected, cell adhesion molecules have an important role in axon–Schwann cell adhesion and myelination. The cell adhesion molecules L1 and NCAM are expressed on nonmyelinated axons, and they are downregulated during early myelination. MAG, a cell adhesion molecule that promotes association between axon and myelinating Schwann cells, is upregulated immediately after the initial layer of myelin is wrapped around the axon ( Figure 1(b) ). Synthesis of myelin proteins increases, and the mRNAs for myelin proteins, such as myelin basic protein (MBP), become concentrated at distal sites in Schwann cells to provide local synthesis of myelin membrane.

Wrapping the layers of myelin around axons and squeezing the cytoplasm out from between the leaflets requires extensive cell extension and motility, which are regulated by actin–myosin cytoskeletal dynamics ( Figure 1(c) ). The Rho kinase (ROCK) regulates actin–myosin mechanical transduction by activating Rho, and in the absence of ROCK activity, the single myelinating process of a Schwann cell splits abnormally to form many smaller internodes, with resulting deleterious consequences for nerve conduction.

Myelin is promoted by many growth factors, including glial-derived neurotrophic factor (GDNF), NRG-1, myelin basic protein (IGFs), brain-derived neurotrophic factor (BDNF), as well as the sex hormone progesterone and the extracellular matrix molecule laminin. Multiple intracellular signaling pathways are involved, notably PI3K-Akt and cAMP. Myelination by Schwann cells is blocked by Notch activation, the neurotrophin NT-3, as well as by extracellular ATP. The latter is released by axons firing bursts of action potentials. TGF-β also inhibits myelination. Neurotrophins such as nerve growth factor (NGF) promote neuronal survival, but NGF stimulates myelination by Schwann cells through an indirect effect on axons. Indirect signals from the axons must be involved because experiments have shown that Schwann cell myelination of types of axons that are not depend on NGF for survival is unaffected by experimental manipulation of NGF.

The thickness of the myelin layer is precisely regulated in proportion to the axon diameter. Axons of larger caliber have thicker myelin, but the ratio of axon diameter to total diameter of axons including the myelin sheath falls within a range of 0.6 to 0.7 (g-ratio), regardless of the diameter of a myelinated axon. How the Schwann cell maintains this strict proportionate myelin thickness to varying axon caliber is unknown, but the thickness can be altered experimentally. BDNF, p75 neurotrophin receptor, or neuregulin overexpression results in abnormally thick myelin. Conversely, if ErbB receptors in Schwann cells are eliminated after myelination has begun, the sheath does not develop to its normal thickness. Myelin on axons regenerated after injury is typically thinner than normal, however.

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Purinergic Signaling

Philip G. Haydon , George J. Siegel , in Basic Neurochemistry (Eighth Edition), 2012

Myelination and importance of the axonal release of ATP

Myelination in both the peripheral and central nervous system is essential for the support of effective axonal propagation. It is perhaps not surprising therefore that there is an activity-dependent regulation of myelination. Neural activity can lead to a non-synaptic release of ATP ( Fields & Ni, 2010). Moreover, this purinergic signal regulates the differentiation of Schwann cells and oligodendrocytes, the peripheral and central sources of myelin. Interestingly, the types of purinergic receptors expressed by Schwann cells and oligodendrocytes are different. Thus although Schwann cells express P2 receptors, they do not express P1 receptors, whereas in contrast, oligodendrocytes express all four P1 receptors. Concordant with this differential receptor expression, these cell types express differential responses to axonal activity. Activity-dependent release of ATP causes a P2 receptor-dependent inhibition of Schwann cell proliferation, differentiation and myelination (Stevens & Fields 2000). In contrast, the activity-dependent release of ATP stimulates a differentiation of oligodendrocytes that is mediated by P1 receptors (Stevens et al., 2002).

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Pediatric Neurology Part III

Andreas Schulze , in Handbook of Clinical Neurology, 2013

GAMT

Delayed myelination and/or bilateral hyperintensity in the globus pallidus are common findings. The earliest changes were observed 17 months after onset of symptoms. In some patients, pallidal changes occur after retarded myelination has resolved. There is no correlation of MRI findings to either the duration or the severity of the disease. MRI abnormalities were observed in five out of eight patients ( Schulze et al., 2003). In a series of 22 patients, six had abnormal bilateral signal intensity in pallidum, the remainder either had delay of myelination or were normal (Mercimek-Mahmutoglu et al., 2006b). Another series of seven patients revealed a normal MRI in four patients and abnormalities in three patients, one with pallidal changes, one with small corpus callosum and delayed myelination and pallidal changes, and one with 2   mm   T2 hyperintensity in the pons (Dhar et al., 2009).

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