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Myelination of the Nervous System: Mechanisms and Functions

Article in Annual Review of Cell and Developmental Biology · October 2014

DOI: 10.1146/annurev-cellbio-100913-013101 · Source: PubMed

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 Myelination of the nervous system: mechanisms and functions

Klaus-Armin Nave and Hauke B. Werner

Corresponding authors: Klaus-Armin Nave, Hauke B. Werner

Max Planck Institute of Experimental Medicine
Department of Neurogenetics
Hermann-Rein-Str. 3
D-37075 Göttingen, Germany
Tel: +49 (551) 3899-759
Fax: +49 (551) 3899-758
E-mail: nave@em.mpg.de, hauke@em.mpg.de

Running title: Myelinating cells

Keywords: Oligodendrocyte; Schwann cell; myelin sheath; neural plasticity; brain energy
metabolism; axon-glia signaling

This is an author-generated pdf version of an article that has been published in

revised form:
Annu Rev Cell Dev Biol. 2014;30:503-33, doi: 10.1146/annurev-cellbio-100913-013101.
The final published version is available at:
http://www.annualreviews.org/doi/full/10.1146/annurev-cellbio-100913-013101
or upon request from the authors.
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Content

(1) INTRODUCTION

(2) CELLULAR MECHANISMS OF MYELINATION

Establishing glia-axonal contact, process polarization, and myelin expansion
Association of major myelin lipids and proteins during membrane growth
Myelin compaction
Myelin cytoskeleton
Myelin-associated inhibitors and the spatial segregation of myelin segments
The myelin proteome

(3) MOLECULAR CONTROL OF MYELINATION

Regulation of peripheral myelination
Regulation of central myelination
Cell-autonomous and epigenetic control of myelination

(4) CELLULAR INTERACTIONS AND COOPERATION IN WHITE MATTER TRACTS

Glia-axonal signaling and support
Metabolic coupling of axons and oligodendrocytes

(5) MYELIN DISEASE

Leukodystrophies
Neuropathies
Demyelinating diseases associated with neuroinflammation

(6) MYELIN PLASTICITY AND AGEING

Oligodendroglial heterogeneity
Oligodendroglial plasticity

 
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ABSTRACT

Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse

propagation, one of the best understood concepts in neurophysiology. However, it took long

to recognize the mechanistic complexity of myelination by oligodendrocytes and Schwann

cells, and of their cellular interactions. In this review we highlight recent advances in our

understanding of myelin biogenesis, its life-long plasticity, and the reciprocal interactions of

myelinating glia with the axons they ensheath. In the central nervous system, myelination is

also stimulated by axonal activity and astrocytes, whereas myelin clearance involves

microglia/macrophages. Once myelinated, the long-term integrity of axons depends on glial

supply of metabolites and neurotrophic factors. The relevance of this axo-glial symbiosis is

illustrated in normal brain aging and human myelin diseases, which can be studied in

corresponding mouse models. Thus, myelinating cells serve a key role in preserving the

connectivity and functions of a healthy nervous system.

(1) INTRODUCTION

Motor, sensory, and cognitive functions of the nervous system require rapid impulse

propagataion, which in vertebrates is facilitated by the insulation of axons with myelin. The

ensheathment of axons by this multilayered glial membrane reduces the transverse

capacitance and increases the transverse resistance of the axonal plasma membrane (Hartline

& Colman 2007). By restricting action potentials to short unmyelinated axonal segments (the

nodes of Ranvier), myelin provides the structural basis for ‘saltatory’ action potential

propagation (Tasaki 1939), which accelerates nerve conduction 20-100-fold compared to

non-myelinated axons of the same diameter - without occupying much space.

By electron microscopy (Figure 1), the much longer axonal segments between two nodes of

Ranvier (‘internodes’) at first glance appear similar in myelinated nerves of the peripheral and

the central nervous system (PNS and CNS). However, Schwann cells and oligodendrocytes,

the respective myelinating glial cells, differ in developmental origin (neural crest versus

subventricular zone), the number of myelinated axonal segments (1:1 versus up to 1:60),

and the myelin periodicity (17nm versus 15.5nm). Moreover, ‘Schmidt-Lanterman incisures‘,

providing cytosolic channels through compact myelin, are only found in adult peripheral

nerves, whereas 'radial components' are tight junction strands specific to CNS myelin (Arroyo

& Scherer 2000, Hildebrand et al 1994, Hildebrand et al 1993). There are also differences

with respect to the composition of structural myelin proteins and the control of myelination,

 
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as highlighted in this article. The similar-appearing structure and function of peripheral and

central myelin is thus a striking example of convergent cellular evolution.

In the evolution of vertebrates, myelin has emerged in cartilaginous fish (Zalc et al 2008)

over 500 million years ago. At that time, all or most myelin constituents and regulators have

been recruited from other cellular functions (Li & Richardson 2008, Werner 2013).

Invertebrates and non-jawed vertebrates can achieve a more rapid impulse propagation by

enlarging the axonal diameter. However, these species possess only a few ‘giant’-diameter

axons for specific reflexes. Yet, an equivalent of myelin exists also in some invertebrate

groups (Hartline & Colman 2007). For example, ‘myelin’ accelerates the escape-response of

small crustaceans (calanoid copepods) that dominate oceanic zooplankton (Lenz et al 2000),

apparently an evolutionary advantage in this hazardous ecosystem. Notably, copepod

‘myelin’ is of axonal rather than glial origin (Wilson & Hartline 2011).

It has been frequently stated that myelination ‘saves energy’. Indeed, the restriction of

action potentials to nodes of Ranvier reduces the need for ATP-dependent Na+/K+-exchange

in maintaining the resting potential of axonal membranes. Saving such energetic costs has

been considered a major benefit in the evolution of myelin (Wang et al 2008). However, it

has also been questioned whether myelination is worth this ‘investment’ from a purely

energetic point of view. A theoretical calculation of the energy balance for the optic nerve

suggested that more ATP is used for myelin biogenesis and maintaining oligodendrocytes

than can be saved by myelin (Harris & Attwell 2012). While there may be region-specific

differences of key variables (axon diameter, internodal length, firing rates), this calculation

supports the concept that the prime advantage of myelin is rapid nerve conduction.

In addition to electrically insulating axons, oligodendrocytes provide trophic axonal support.

This function appears particularly relevant for longer axons, in which some segments are

many centimeters (or even meters) away from the neuronal soma but in close contact to

local glial cells. Indeed, there is accumulating evidence that the energy metabolism of axons

is coupled to that of myelinating glia.

Here, we will first review the cellular and molecular mechanisms of myelin biosynthesis. Insight

into the mechanisms underlying myelination has greatly progressed, including the axonal cues

that ‘remote-control’ the behavior of glial cells for the benefit of the myelinated neuron itself,

the development of glial progenitor cells, and the process of myelin membrane wrapping. We

will then discuss recent advances in understanding the metabolic interactions between

 
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myelinating cells and myelinated axons. We will close this review with a look at the role of

myelin in neuropsychiatric diseases and the impact of oligodendrocytes on neuroplasticity and

brain aging. We would like to refer the reader to previous review articles for the related topics

of remyelination in pathological situations (Fancy et al 2011, Kotter et al 2011) and node

assembly (Salzer et al 2008, Zollinger et al 2014), which we will not cover in depth.

(2) CELLULAR MECHANISMS OF MYELINATION

By electron microscopy (Figure 1), myelin is the spiral extension of a glial plasma membrane

that is visualized by electron-dense 'major dense lines' (MDL) and 'intraperiod lines' (IPL) at

the compacted intracellular and extracellular membrane surfaces, respectively. However,

myelin also comprises a continuous network of uncompacted cytosolic compartments, such

as the innermost (adaxonal) and outermost (abaxonal) layers, which are radially connected by

Schmidt-Lanterman incisures (in the PNS) and the paranodal loops (Arroyo & Scherer 2000,

Bunge 1968, Hildebrand et al 1994, Hildebrand et al 1993, Nave 2010). Visualizing the

morphogenesis of myelin has been a challenge but has greatly progressed with the recent

application of new imaging techniques.

Establishing glia-axon contact, process polarization, and myelin expansion

Unlike their small proliferative precursor cells, committed oligodendrocyte progenitors (OPC)

are multipolar cells, the function of which is not completely understood. OPC remain motile and

can migrate in the CNS, thereby 'tiling' the brain. Their processes do not intermingle but rather

extend and retract like filopodia (Kirby et al 2006) (Figure 2) with a dynamics that is

maintained in adult OPC (Biname et al 2013, Hughes et al 2013, Young et al 2013). Upon first

contact with an axonal membrane, the tip of the OPC process is either retracted or stabilized. If

stabilized, a specialized membrane domain for continued axon-glial communication is formed,

although it is unclear which (if any) of the glial adhesion proteins stabilize these contacts.

The initial contact induces a number of molecular rearrangements in the future myelinating

cell (Figure 2), including the association of the tyrosine-kinase fyn with lipid-rich membrane

microdomains (Czopka et al 2013, Krämer-Albers & White 2011), the suppression of RhoA-

activity (Baer et al 2009), and the local enrichment of phosphoinositides in the glial

membrane, i.e. phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidylinositol-3,4,5-

trisphosphate (PIP3) (Goebbels et al 2010, Goebbels et al 2012, Snaidero et al 2014).

Moreover, the localization and activity of ‘polarity proteins’ changes (Chan et al 2006,

Etienne-Manneville 2008, Ozcelik et al 2010), ‘directed’ mRNA-transport and local protein

 
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translation is activated (Barbarese et al 1999, Müller et al 2013, Wake et al 2011), and

cytoskeletal elements are reorganized (see below). Together, these changes establish a

polarization of myelinating cells towards the axon, which is now considered a crucial phase of

myelination (Baron & Hoekstra 2010, Ozcelik et al 2010).

In postnatal development, the myelin membranes of an oligodendrocyte may grow by as much

as 5000 µm2 per day (Pfeiffer et al 1993). Mature myelin consists of up to 160 membrane

layers, and internodes extend up to 1.7 mm in the CNS and up to 2 mm in the PNS (Hildebrand

et al 1994, Hildebrand et al 1993). Most of the longitudinal expansion of a myelin segment

('internode') coincides with secondary axon elongation during body growth (Simpson et al

2013), which takes months and years in humans. In contrast, internodes are formed within a

few days, raising the question how the radial and longitudinal expansion of myelin are

coordinated (Bauer et al 2009, Rosenbluth 1999, Sobottka et al 2011). Indeed, the various

models of myelination, originally built on two-dimensional electron micrographs (Figure 1),

have left crucial aspects unexplained. Recently, in vivo time-lapse imaging of zebrafish embryos

and quantitative analysis of electron micrographs from optic nerve serial sections have added

temporal and three-dimensional resolution to the visualization of developmental myelination

(Snaidero et al 2014). According to this model, radial and longitudinal sheath expansion occur

fairly simultaneously as new membrane is continuously added at the growing tip of the inner

tongue (Figure 2). The innermost layer of the sheath is at the same time laterally expanding

and squeezes in between the preceding layer and the axon, an event commonly termed

‘wrapping’. The addition of membrane at the growing tip requires the cytosolic (‘myelinic’)

channels to remain sufficiently wide open (see also below). Molecular aspects of the vesicular

trafficking of prospective myelin membrane through the secretory pathway as well as

endocytic membrane recycling have been reviewed (White & Kramer-Albers 2014).

Association of major myelin lipids and proteins during membrane growth

Compared to other plasma membranes, myelin has a very high lipid content, i.e. 70–75% of

its dry weight, and an unusual lipid composition with a molar ratio of about 2:2:1:1 for

cholesterol : phospholipids : galactolipids : plasmalogens (Norton & Poduslo 1973a). Myelin

lipids have a high lateral mobility (Gould & Dawson 1976), and it is thought that the

cholesterol content limits the membrane’s fluidity, thereby affecting its intracellular

trafficking and myelin compartmentalization (Maxfield & van Meer 2010, Rosetti et al 2008,

Yurlova et al 2011). With over 25% of total myelin lipid, cholesterol is about two-fold

'enriched' in myelin compared to other plasma membranes, in which cholesterol is 5-10 fold

more abundant than in the endoplasmic reticulum (van Meer et al 2008). This suggests that

 
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prospective myelin membranes expand by the coalescence of cholesterol-rich membrane-

microdomains in the secretory pathway of the glial cell (Chrast et al 2011, Lee 2001).

Indeed, cholesterol is rate-limiting for myelination, as demonstrated in mutant mice or

zebrafish that lack an essential enzyme for cholesterol biosynthesis (Mathews et al 2014,

Saher et al 2005, Saher et al 2009). Interestingly, myelination continues at a slow pace in

the CNS of mice lacking oligodendroglial squalene synthase/Fdft1, probably due to horizontal

cholesterol flux from neighboring astrocytes (Carmago, Verheijen et al., under review).

Cholesterol-rich membrane-microdomains have a high affinity to proteolipid protein (PLP)

(Simons et al 2000, Werner et al 2013) and protein zero (P0/MPZ) (Hasse et al 2002, Saher

et al 2009), the dominant membrane proteins of central and peripheral myelin, respectively

(Jahn et al 2009, Patzig et al 2011) (see also Table 1). The high concentration of

cholesterol in CNS myelin purified from Fdft1-mutant mice (Saher et al 2005) has suggested

that proteolipids serve to enrich membrane-cholesterol. Indeed, PLP-deficiency in mice

reduces the abundance of cholesterol in myelin (Werner et al 2013).

Perturbed cholesterol synthesis in Schwann cells impairs the transport of P0 from the

endoplasmic reticulum into the myelin compartment (Saher et al 2009). Likewise, the

abundance of MAL (myelin and lymphocyte protein) in CNS myelin depends on a myelin-

enriched lipid (3-O-sulfogalactosylceramide, SGalC) (Saravanan et al 2004). Intriguingly, mice

lacking MAL or SGalC display similar paranodal abnormalities, at least in the CNS (Marcus et al

2006, Schaeren-Wiemers et al 2004). However, the specific molecular functions of several

classes of myelin-enriched lipids, including galactolipids (Coetzee et al 1996, Eckhardt 2008)

and plasmalogens (Rodemer et al 2003), remain to be defined.

Myelin compaction

The compaction of multiple membrane layers, as seen by electron microscopy (Figure 1),

progresses from the abaxonal layers towards the (adaxonal) inner tongue with a delay of 2-3

wraps behind the leading edge (Hildebrand et al 1993, Snaidero et al 2014), allowing the

growing sheath to expand underneath the previous layer. This compaction requires

specialized adhesive proteins and the removal of molecules that prevent compaction. Initially,

the intracellular surface of the glial membrane is inhibitory to tight appositions due to highly

charged phospholipids, such as PIP2. However, negatively charged membrane surfaces attract

basic proteins, such as myelin basic protein (MBP) (Harauz et al 2009). MBP is an abundant

protein (8% by mass; Table 1) with high affinity to PIP2 (Musse et al 2008, Nawaz et al

2009, Nawaz et al 2013). Microtubule-dependent transport of mbp-mRNA into

 
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oligodendroglial processes (Barbarese et al 1999, Colman et al 1982) and inhibition of

premature translation are under elaborate molecular control (Müller et al 2013, Torvund-

Jensen et al 2014). By neutralizing membrane phospholipids, MBP pulls together two bilayers

similar to a zipper (Aggarwal et al 2013), which forms the MDL and allows myelin to grow

(Min et al 2009). Oligodendrocytes that lack MBP, e.g. in shiverer mice (Roach et al 1985),

fail to form compact myelin and remain severely dysmyelinated. While MBP is rate-limiting for

CNS myelination (Readhead et al 1987), peripheral myelination can proceed without the

incorporation of MBP (Kirschner & Ganser 1980), which is compensated by the basic

intracellular domain of P0 (Martini et al 1995) and, possibly, by protein 2 (P2/Pmp2)

(Ruskamo et al 2014, Suresh et al 2010).

Extracellular compaction of myelin membranes in the PNS requires the homotypic interactions

of P0, a cell adhesion protein with a single immunoglobulin-like domain (Filbin et al 1990,

Giese et al 1992). P0 is absent from central myelin in tetrapods (Yin et al 2006, Yoshida &

Colman 1996). Here, adhesive properties have been ascribed to PLP (Rosenbluth et al 2006),

an abundant tetraspan that lacks a typical signature domain of adhesion proteins. Indeed, the

adhesive properties of PLP are subtle compared to P0 (Bakhti et al 2013, Bizzozero et al

2001, Rosenbluth et al 2006), and it has been discussed whether they contribute to myelin

compaction in vivo at all (Bakhti et al 2013, Möbius et al 2008). Moreover, the lack of PLP is

partly compensated by its close homolog GPM6B (Werner et al 2013). However, the common

function of both proteolipids relates to the trafficking of prospective myelin membranes in

the oligodendroglial secretory pathway rather than myelin compaction.

In the CNS, adhesive forces between adjacent myelin layers converge at the 'radial

component' (Rosenbluth et al 2006, Rosenbluth et al 2009), serial tight junction strands

undulating through compact central myelin (Peters 1961). The radial component is primarily

comprised of claudin-11 (Cldn11), an abundant myelin protein (Table 1). Cldn11–deficient

mice lack this radial component and display decelerated nerve conduction (Devaux & Gow

2008, Gow et al 1999). Hypothetically, the concentration of adhesive forces may allow more

flexibility than P0-mediated adhesion for adjacent membrane bilayers to resume myelin

growth and to adapt myelin sheath thickness throughout adult live, which appears possible in

the CNS but not in the PNS (Goebbels et al 2012).

Cytoplasmic continuity between the glial cell body and the non-compacted adaxonal myelin

layer is provided by the paranodal channels, which remain non-compacted throughout live.

Additional cytoplasmic channels (Schmidt-Lanterman incisures) exist life-long in the

 
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internodal segment of peripheral myelin but are largely closed during the maturation of CNS

myelin (Arroyo & Scherer 2000, Velumian et al 2011) (Figure 2). However, during early

CNS myelination, these radial cytoplasmic channels remain open, thereby providing routes for

the vesicular trafficking towards the growth zone at the inner tongue (Snaidero et al 2014).

Here, absence of cyclic nucleotide phosphodiesterase (CNP) accelerates the MBP-mediated

developmental closure of these incisures. It is yet unclear whether normal channel closure

involves CNP’s enzymatic or microtubule-modifying activities (Lee et al 2005, Verrier et al

2013), or whether CNP is simply difficult to displace due to its abundance (Table 1), size, or

ability to dimerize (Myllykoski et al 2012).

Generally, molecules with cytoplasmic domains larger than those of a certain threshold size

do not enter mature myelin and are therefore driven out during compaction (Aggarwal et al

2011). Moreover, forced attachment of a polysialic acid extracellular moiety to proteins

normally incorporated into the growing sheath is inhibitory to efficient myelination (Bakhti et

al 2013, Fewou et al 2007). Thus, glycosylated proteins are generally absent from compact

CNS myelin. Interestingly, this is in marked difference to compacted peripheral myelin, which

harbors two abundant glycoproteins, P0 and PMP22. Why these space restrictions are more

critical in the CNS (myelin period 15.5 nm) compared to the PNS (17 nm) is unknown.

Myelin cytoskeleton

The regulation of stability and shape of cytoskeletal filaments is an important downstream-

effect of molecular signaling in myelinating glia. Actin filaments (F-actin) are crucial for the

motility of cellular processes, intracellular transport, and mechanical properties of membranes.

The actin cytoskeleton is required for process expansion during myelin biogenesis, as shown in

mice lacking actin filament-regulating proteins, including WAVE1/Wasf1 (Kim et al 2006) or N-

WASP/Wasl (Jin et al 2011, Novak et al 2011) in oligodendrocytes and Schwann cells.

Vesicular trafficking of prospective myelin membranes involves the motor protein myosin-5a

(Myo5a), at least in oligodendrocytes (Sloane & Vartanian 2007). Lack of Myo5a from OPC and

oligodendrocytes impairs the conversion of filopodia into lamellipodia and thus myelination.

When actin filaments were disrupted in myelinating cocultures in vitro by an inhibitor of

polymerization (Cytochalasin D), the compartmentalization of the abaxonal layer of peripheral

myelin (into 'bands of Cajal') was impaired (Court et al 2009), indicating that actin filaments

shape the ultrastructure of myelinated fibers.

Filamentous actin is not particularly abundant in mature oligodendrocytes (Capani et al

2001), and α-actin can hardly be detected in purified CNS myelin (Jahn et al 2013),

 
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reflecting a diminishment of process motility during myelin maturation. After myelin

compaction, microfilaments are restricted to non-compacted compartments, in which they

may serve a function in myelin maintenance and turnover.

The main class of cytoskeletal elements in mature oligodendrocytes and Schwann cells are

microtubules that can be readily seen in non-compact myelin by electron microscopy (Kidd et

al 1994, Lunn et al 1997). During myelination, microtubules provide trafficking routes for

transport vesicles (Pfeiffer et al 1993) and mbp-mRNA (Müller et al 2013). In zebrafish,

tubulin alpha 8-like 3a (tuba8l3) (Larson et al 2010) and the tubulin-associated motor-

protein Kif1b (Lyons et al 2009) were identified as key components of myelination.

Recently, also intermediate filaments were found involved in maintaining the ultrastructure of

myelin, at least in the PNS. Lack of vimentin (Vim) or its associated linker protein plectin

(Plec) resulted in increased thickness of peripheral myelin and impaired long-term integrity,

respectively (Triolo et al 2012, Walko et al 2013). Nevertheless, the overall abundance of

actin, tubulin, and intermediate filament proteins in myelin is relatively low (Jahn et al 2013).

In contrast, septins, which constitute a fourth class of filament-forming proteins, are quite

abundant. Localized to non-compact myelin (Buser et al 2009, Ogawa & Rasband 2009), the

function of myelin-associated septins remains to be determined (Patzig et al 2014).

Cytoskeleton-associated proteins are among the most abundant myelin constituents,

including CNP, the deacetylase sirtuin-2 (Sirt2) (Beirowski et al 2011, Southwood et al 2007,

Werner et al 2007), tubulin-polymerization promoting protein (Tppp) (Hoftberger et al

2010), as well as cofilin (Cfl1) (Sparrow et al 2012) and ermin/juxtanodin (Ermn)

(Brockschnieder et al 2006, Ruskamo et al 2012), two modulators of actin polymerization.

Considering the large number of abundant cytoskeletal proteins identified in myelin by

proteome analyses (see below), much more remains to be learned about the relevance of the

cytoskeleton in myelin.

Myelin-associated inhibitors and the spatial segregation of myelin segments

It is well known that myelin comprises several growth inhibitory molecules, which are of

interest in the context of CNS injury and axonal regrowth in the injured mammalian CNS

(Filbin 2003). At least three protein groups comprise repulsive oligodendrocytic surface

molecules, i.e. the myelin-associated inhibitors (Nogo/Rtn4, MAG, OMG), classical axon-

guidance molecules (semaphorins, ephrins, netrins), and chondroitin sulfate proteoglycans

(CSPG). Myelin lipids can also inhibit axonal growth (Winzeler et al 2011), though their

 
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physiological functions are not well understood. Myelin-associated molecules, such as class 3-

semaphorins (Piaton et al 2011, Syed et al 2011) and Nogo (Chong et al 2012), can direct

the migration and differentiation of OPCs, thereby controlling the spatial arrangement of

oligodendrocytes. Strikingly, Nogo has also been implicated in the lateral segregation of

neighboring internodes competing for axonal surface, both during developmental myelination

and remyelination. Indeed, myelin-associated inhibitors affect the number of internodes

formed by a particular oligodendrocyte (Chong et al 2012). Myelin-associated inhibitors are

also candidates to prevent the pathological double-myelination of already ensheathed axons

and to assure that nodes of Ranvier are left unmyelinated. The interest in myelin inhibitors

has thus extended from their role in spinal cord injury to their function in guiding OPCs for

repair in demyelinating conditions (Fancy et al 2011, Kotter et al 2011), and their role in

normal CNS development and plasticity (Chong et al 2012, McGee et al 2005).

The myelin proteome

Exploiting its low physical density as a membrane, myelin can be biochemically purified from

nervous tissue (Norton & Poduslo 1973b). More recently, the technique has allowed a

systematic investigation of the protein content of myelin by mass spectrometry. While only

one proteomic study of peripheral myelin is available (Patzig et al 2011), the published

datasets for central myelin have allowed a meta-analysis of the >1000 proteins identified

thus far (de Monasterio-Schrader et al 2012). Technical advances and new scientific

questions led to novel datasets (Dagley et al 2014, Manrique-Hoyos et al 2012), further

increasing the number and validity of identified proteins. Together, these efforts have

established that myelin comprises considerably more proteins than previously anticipated,

many of them being low-abundant constituents localized to the non-compact myelin

compartments. Also the relative abundance of the major myelin proteins has been reassessed

(Jahn et al 2009, Patzig et al 2011) using quantitative mass spectrometry (Table 1).

More importantly, the myelin proteome has supported the selection of proteins for functional

investigations in mutant mice, the integration with the oligodendroglial transcriptome (Cahoy

et al 2008, de Monasterio-Schrader et al 2012), the calculation of molar ratios (Sherman et

al 2012), analyses of pathological conditions (Derfuss et al 2009, Fewou et al 2010, Martins-

de-Souza et al 2011, Patzig et al 2011, Werner & Jahn 2010, Werner et al 2007), and the

discovery of disease-causing genes (Soong et al 2013). Indeed, many of the newly identified

myelin proteins probably serve functions in preserving a healthy nervous system, rather than

in myelin biogenesis itself.

 
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(3) MOLECULAR CONTROL OF MYELINATION

Prospective myelin-forming glial cells follow an intrinsic program of proliferation, migration, and

differentiation, which is controlled by exogenous signals, including axonal cues (Almeida et al

2011). Detailed reviews on the development of Schwann cells (Jessen & Mirsky 2005, Pereira

et al 2012, Taveggia et al 2010) and oligodendrocytes (Ahrendsen & Macklin 2013, Mitew et

al 2013) are available, which also cover the relevant intracellular signaling cascades. Here, we

focus on the exogenous cues affecting the last step of differentiation, i.e. myelination itself.

Regulation of peripheral myelination

Axon caliber is a key signal for myelination by Schwann cells, and the threshold diameter is

rather invariable (1µm), as is the numerical ratio between axon diameter and diameter of the

axon/myelin-unit (g-ratio=0.68), a measure of myelin thickness. It is well known that

receptor tyrosine-kinases (erbB2, erbB3), expressed on Schwann cells (Lyons et al 2005,

Riethmacher et al 1997, Woldeyesus et al 1999), can sense and integrate the abundance of

neuregulin-1 (NRG1-type III) on the axonal surface (Michailov et al 2004, Taveggia et al

2005), a measure of its diameter. Modulators of NRG1–ErbB signaling include glial scaffolding

proteins (e.g. erbB2-interacting protein/Erbb2IP) (Tao et al 2009), the tyrosine phosphatase

Shp2/Ptpn2 (Grossmann et al 2009), and the neuronal proteases BACE1 and TACE/Adam17

(Hu et al 2006, La Marca et al 2011, Velanac et al 2012, Willem et al 2006). By BACE1-

dependent cleavage of NRG1-type III, its extracellular epidermal growth factor (EGF)-like

signaling domain is exposed at the axonal surface. However, the balance between the use of

two alternative proteolytic cleavages determines whether BACE1 activates or TACE inhibits

NRG1-type III activity and peripheral myelination.

A genetic screen in zebrafish (Pogoda et al 2006) identified the G-protein coupled receptor

GPR126 as essential for peripheral myelination (Monk et al 2009). Importantly, its function is

largely conserved between fish and mice (Monk et al 2011). Probably following the binding of

an (unknown) axonal ligand, GPR126 acts through elevating cAMP-levels in Schwann cells

(Mogha et al 2013). While it well known that raised cAMP-levels are crucial for Schwann cell

development in vitro (Jessen et al 1991), the underlying molecular mechanisms have

remained unknown. Recently, adenylate cyclase-6 (ADCY6) was identified as critical for

peripheral myelination in zebrafish and with mutations causing axoglial defects in human

patients (Laquerriere et al 2014). However, a direct molecular link between GPR126 and

ADCY6 has not yet been reported.

 
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Several other signaling systems modulate peripheral myelination, including promyelinating

BDNF signaling via neurotrophin receptors (Chan et al 2004, Cosgaya et al 2002) and

negative regulation by Notch signaling in Schwann cells (Woodhoo et al 2009). Myelination is

also enhanced by N-Cadherin (Wanner & Wood 2002), beta1-Integrin (Feltri et al 2002), and

the Schwann-cell derived Lgi4 (leucine-rich glioma-inactivated-4), which is a 'leucin-rich

glioma activated' protein that interacts with the axonal protease ADAM22 (Kegel et al

2014). Other membrane proteins are required for the normal structure of peripheral myelin

rather than membrane biogenesis, including the prion protein/Prnp localized on axons

(Bremer et al 2010) and the glial cell adhesion molecule NECL4/Cadm4 (Golan et al 2013).

Considering the complexity of axo-glial signaling systems, it remains an important goal to

further delineate their interdependence, i.e. which molecules act upstream, downstream, or

independent of each other. Indeed, the integration of exogenous signals may largely be

integrated at the level of converging intracellular signaling cascades toward the Schwann cell

nucleus (Jessen & Mirsky 2005, Pereira et al 2012, Taveggia et al 2010).

Regulation of central myelination

For oligodendrocytes, the threshold axonal diameter to myelinate is more variable (0.4-1.2

µm) than for Schwann cells, and may be as low as 0.2 µm (Lee et al 2012a). This reflects

that myelination in the CNS is promoted by numerous factors, including electrical activity

(Wake et al 2011), the spatial density of OPCs (Rosenberg et al 2008), and cues from

astrocytes (Back et al 2005, Hammond et al 2014) and microglial cells (Miron et al 2013,

Yuen et al 2013). Thus, oligodendrocytes are less dependent than Schwann cells on cues

received from single axons.

For example, CNS myelination can proceed upon the experimental absence of neuronal NRG1-

expression or oligodendroglial erbB3 and erbB4 signaling (Brinkmann et al 2008), while NRG1-

overexpression or BDNF signaling to tyrosine kinase receptors (trkB) can stimulate

myelination by oligodendrocytes (Brinkmann et al 2008, Taveggia et al 2008, Wong et al

2013). Recently, it has been suggested that NRG1 signaling to oligodendrocytes triggers a

switch from CNS myelination 'by default' to glutamatergic regulation (Lundgaard et al 2013).

Similar to the PNS, it is a topic of current analyses how and at which cellular level the various

oligodendroglial signaling cascades are integrated towards regulating the expression of genes

required for the synthesis of myelin proteins and lipids (Ahrendsen & Macklin 2013, Mitew et

al 2013). For example, it will be important to determine how signaling via fibroblast growth

 
   13  

factor receptors (Fgfr) (Furusho et al 2012, Furusho et al 2011) converges with erbB- and

trk-receptor signaling.

When considering the local induction of myelin biogenesis, it appears equally relevant to

reflect the cues actually inhibiting myelination (Harlow & Macklin 2014). Indeed,

oligodendroglial maturation and thus myelination are controlled by negative regulators,

including the neuronal surface molecules PSA-NCAM (Charles et al 2000) and LINGO1

(leucine-rich repeat and Ig-domain-containing-1) (Lee et al 2007), the neurotrophin nerve

growth factor (NGF) (Chan et al 2004), the oligodendroglial GPR17 (Chen et al 2009), and

the astroglia-derived extracellular matrix molecule hyaluronan (Back et al 2005). Such factors

may also prevent that cellular structures other than axons are myelinated.

Cell-autonomous and epigenetic control of myelination

The expression of myelin-related genes is controlled by transcriptional master-regulators,

both in oligodendrocytes (SOX10, MYRF, YY1, SIP1/Zeb2) (Emery et al 2009, He et al 2007,

Stolt et al 2002, Weng et al 2012) and Schwann cells (SOX10, KROX20/Egr2, OCT6/Pou3f1)

(Bermingham et al 1996, Finzsch et al 2010, Topilko et al 1994). More recently, it became

evident that their activities are associated with regulatory networks involving chromatin

remodeling, histone modifications, and DNA methylation (Liu & Casaccia 2010) . Importantly,

there is not necessarily a direct correlation between the transcriptional rate of a myelin-

related gene and the abundance of its protein product, as regulatory RNAs affect the

stability of mRNAs (Barca-Mayo & Lu 2012).

Together, these studies have shaped the view that the cell-autonomous program of

myelination involves both, the transcriptional activation of myelin-related genes and the

simultaneous de-repression of factors counteracting their expression (Liu & Casaccia 2010,

Swiss et al 2011). A better understanding of the molecular cascades underlying epigenetic

changes in myelinating cells holds great promise for enhancing remyelination in pathological

states (Huynh et al 2014).

(4) CELLULAR INTERACTIONS AND COOPERATION IN WHITE MATTER TRACTS

A critical aspect of developmental myelination is the formation of septate-like axo-myelinic

junctions at the paranodal segment, which separate the voltage-gated sodium channels at

the node of Ranvier from the juxtaparanodal and the internodal axolemma (Salzer et al

2008). The current concepts of this glia-dependent (Kaplan et al 1997) molecular assembly

 
   14  

and its relevance for channel clustering and nerve conduction are discussed separately in this

issue of Annual Review of Cell and Developmental Biology (Zollinger et al 2014). Myelinating

cells also affect axonal diameter and transport (de Waegh et al 1992, Edgar et al 2004, Yin

et al 1998), both during development and in mature animals.

Different from the PNS, degenerated axons regenerate only poorly in the CNS (Brosius Lutz &

Barres 2014). This has fostered substantial interest in the intrinsic (Wang et al 2012) and

extrinsic (Nave 2010) mechanisms detrimental or beneficial for preserving axonal integrity.

For example, axonal spheroids were frequently seen in the white matter tracts of mice lacking

the myelin proteins PLP (de Monasterio-Schrader et al 2013, Griffiths et al 1998) or CNP

(Edgar et al 2009) or functional oligodendroglial peroxisomes (Kassmann et al 2007). Even

experimentally-induced oligodendrocyte death primarily leads to axonal degeneration while

the ultrastrucure of myelin is initially spared and immune cells remain comparatively

unresponsive (Locatelli et al 2012, Oluich et al 2012, Pohl et al 2011). Thus, after

maturation, the integrity and survival of myelinated axons depends on oligodendroglial

support. Notably, the formation of an axonal spheroid (or “swelling”) may not necessarily

lead to complete axonal degeneration (Nikic et al 2011), raising hope that it is principally

possible to therapeutically support axonal integrity in demyelinating disorders.

Glia-axonal signaling and support

When aiming at counteracting axon degeneration, it is thus important to better understand

the interactions between myelinated axons and their associated myelinating cells.

Interestingly, the experimental deletion of classical adhesion proteins at the axon-myelin

interface has either not been reported to cause evident axonal degeneration (NECL4/Cadm4)

(Golan et al 2013) or its requirement for axonal integrity is fairly subtle (MAG) (Li et al 1994,

Nguyen et al 2009) compared to that of PLP, CNP, or oligodendroglial peroxisomes.

In the search for alternative routes for myelinating cells to affect axonal functions it was

striking that extracellular vesicles can directly transfer material to axons from both

oligodendrocytes (Frühbeis et al 2013, Krämer-Albers et al 2007) and Schwann cells (Court

et al 2008, Lopez-Verrilli et al 2013). Importantly, the transferred mRNAs and proteins

include promising candidates to locally provide degeneration-preventing or regeneration-

promoting support. Notably, also other cues by myelinating cells have the capacity to

support axons, including glial cell-derived neurotrophic factor (GDNF) (Wilkins et al 2003) or

gap junction-forming connexins. Indeed, CX29/Gjc3 and CX32/Gjb1 are present in adaxonal

myelin (Altevogt et al 2002) and may provide routes for the passage of small metabolites,

 
   15  

notwithstanding that their actual substrates are yet unknown. Mild axonal pathology emerges

upon mutations affecting CX32 in the X-linked form of Charcot-Marie-Tooth disease (CMT1X)

and in null-mutant mice (Anzini et al 1997, Hahn et al 2001). In this model the axonopathy

precedes demyelination (Vavlitou et al 2010), supporting the concept that many myelin

constituents primarily support axonal rather than myelin integrity.

Metabolic coupling of axons and oligodendrocytes

Mitochondria are transported rapidly along axonal internodes but slow down at the nodes of

Ranvier (Misgeld et al 2007). Experimentally enhanced electrical activity further decelerates

mitochondrial transport (Ohno et al 2011), probably reflecting a local requirement for

mitochondria-generated ATP to maintain the ion potential across the axonal membrane.

However, it is not a trivial question how axonal mitochondria gain the pyruvate or lactate

required for oxidative ATP-production.

Glucose is supplied to the brain via blood vessels (Figure 3), from which it is taken up by

endothelial cells to be transferred to astrocytes. In astrocytes, glucose may be stored in the

form of glycogen or undergo glycolysis, i.e. catabolized into pyruvate and lactate (Wiesinger et

al 1997). During myelin biogenesis, oligodendrocytes consume astrocyte-derived lactate as an

energy source for their mitochondrial ATP-production, or, more directly, for the synthesis of

myelin lipids (Rinholm et al 2011, Sanchez-Abarca et al 2001). Strikingly, however,

mitochondria are not required for the maintenance of mature myelin by oligodendrocytes

(Fünfschilling et al 2012), different from Schwann cells (Fünfschilling et al 2012, Viader et al

2011). Oligodendroglial maturation thus coincides with a switch from a requirement for

mitochondrial functions to the ability of pursuing a non-mitochondrial (i.e. glycolytic) energy

metabolism. Importantly, this concept is supported by the finding that axonal integrity is

independent of functional oligodendroglial mitochondria (Fünfschilling et al 2012).

If lactate is not metabolized in the mitochondria of mature oligodendrocytes, what is its

fate? Considering that the inhibition of a glial lactate transporter (monocarboxylate

transporter MCT1/Slc16a1) causes axonal damage and neuron loss (Lee et al 2012b),

lactate has emerged as a key metabolite to be transferred to axons from oligodendrocytes.

Indeed, lactate transport may represent one purpose of the intra-myelinic incisures and gap

junctions. More speculatively, in pathological conditions lactate as an energy source for

axonal mitochondria may even be gained by the breakdown of myelin lipids in oligodendroglial

peroxisomes, i.e. β-oxidation (Kassmann 2014). Notably, lactate is also shuttled to neurons

from astrocytes, at least at glutamatergic synapses in the hippocampus (Suzuki et al 2011).

 
   16  

Considering that MCT1 is expressed by both astrocytes (Rinholm et al 2011) and

oligodendrocytes (Lee et al 2012b), it will be an important future task to determine (by cell-

type specific deletion) their relative contributions to fulfilling neuronal energy demands.

The metabolic exchange between oligodendrocytes and axons is not a one-way route. This is

exemplified by the abundant neuronal metabolite N-acetylaspartate (NAA) (Figure 3). The

enzyme required to catabolize NAA (aspartoacylase/ASPA) is restricted to oligodendrocytes,

and its breakdown product acetate was suggested to be utilized for the biosynthesis of myelin

lipids (Namboodiri et al 2006). Notably, hypomyelination in human patients and experimental

mice is caused by mutations affecting either ASPA or a neuronal aspartate-glutamate carrier

(AGC1/Aralar/SLC25A12) required for the mitochondria-to-cytosol transport of aspartate (Jalil

et al 2005, Kaul et al 1993, Mersmann et al 2011, Wibom et al 2009) before its conversion

into NAA mediated by N-acetyltransferase-8-like (NAT8L) (Wiame et al 2010).

(5) MYELIN DISEASE

Leukodystrophies

Only few of the genes that cause (when mutated) leukodystophies actually encode myelin

proteins. In this respect, the classical example of the PLP1-gene (causative of Pelizaeus-

Merzbacher disease (PMD) or the allelic type-2 spastic paraplegia (Saugier-Veber et al 1994))

is rather the exception. Indeed, leukodystrophies can originate from mutations affecting very

diverse cellular compartments, including peroxisomes, mitochondria, lysosomes, sphingolipid-

metabolism, RNA-metabolism, tRNA-metabolism, and protein translation (Bugiani et al 2010,

Edvardson et al 2008, Gieselmann & Krageloh-Mann 2010, Henneke et al 2009, Mosser et al

1993, Taft et al 2013, Wong 2012). The diversity of causative genes and affected pathways

indicates that no single therapy concept may suit all inherited demyelinating disorders, or not

even all patients with the same disorder. Consequently, promising therapeutic approaches are

rather distinct, such as the downregulation of toxic Plp1-overexpression or cholesterol-

dependent modulation of intracellular PLP-trafficking in PMD (Prukop et al 2014, Saher et al

2012), counteracting oxidative stress in a comparatively mild variant of X-linked

adrenoleukodystrophy (X-ALD) (Morato et al 2013), enzyme replacement in metachromatic

leukodystrophy (MLD) (Stroobants et al 2011), and hematopoietic stem cell therapy in X-

ALD and MLD (Biffi et al 2013, Cartier et al 2009).

Oligodendrocytes are not necessarily the primarily impaired cell type in all leukodystrophies.

This became evident with the identification of disease-causing mutations affecting cell-cell

 
   17  

interactions, such as a gap junction-protein mediating oligodendrocyte-to-astrocyte-coupling

(Cx47/GJC2) (Uhlenberg et al 2004), notwithstanding that its substrate is yet unknown.

Leukodystrophies can even be caused by mutations affecting proteins predominantly

expressed in neurons (FAM126A), microglia (CSF1R), astrocytes (GFAP, MLC1, HEPACAM,

CLCN2), and vascular cells (NOTCH3) (Depienne et al 2013, Erblich et al 2011, Gazzerro et al

2012, Leegwater et al 2001, Lopez-Hernandez et al 2011, Mignot et al 2004, Penton et al

2012). Together, the diversity of affected cell types supports the concept that an intimate

intercellular network is required to maintain white matter integrity. However, proof for the

pathogenic relevance of any particular cell type in leukodystrophies necessitates the analysis

of cell-type-specific mutant mice.

The growing knowledge about leukodystrophy-causative genes and their pathophysiology has

thus emphasized that myelin pathology can be due to non-oligodendroglial causes. On the

other hand it has become evident that oligodendroglial dysfunction can contribute to the

neuropathology in classical neurodegenerative diseases or the respective mouse models. For

example, restored oligodendrocytic expression of MECP2 (methyl-CpG binding protein-2)

improved some deficits in a mouse model of Rett syndrome, while its oligodendrocyte-

specific deletion caused hindlimb clasping (Nguyen et al 2013). In amyotrophic lateral

sclerosis (ALS) patients and a mouse model (SOD1G93A), spinal cord oligodendrocytes

degenerate, while the cell-type specific deletion of mutant SOD improved pathological

parameters and survival (Kang et al 2013). The degeneration of motor neurons may be

related to a reduced abundance of oligodendroglial MCT1 (see above), as seen in ALS

patients and mouse models (Kang et al 2013, Philips et al 2013). Together, oligodendrocyte-

dependent axonal survival and function has emerged as a novel facet in the pathobiology of

several neurodegenerative disorders of the CNS.

Neuropathies

Detailed review articles on the genetics and pathobiology of heritable peripheral neuropathies

collectively termed Charcot-Marie-Tooth disease (CMT) are available (Saporta & Shy 2013,

Timmerman et al 2013). Notably, neuropathies can also be acquired, e.g. by bacterial

infection with Mycobacterium leprae leading to leprosy. The key aspect of the rapid

demyelination appears to be the bacterium activating the erbB2-receptor on Schwann cells

(Tapinos et al 2006), thereby superseeding the normal Nrg1-dependent control of Schwann

cell proliferation and differentiation. Indeed, the leprosy bacterium can induce the

transdifferentiation of myelinating into non-myelinating Schwann cells (Masaki et al 2013), its

preferred niche in peripheral nerves. Notably, transdifferentiation is a normal feature of

 
   18  

Schwann cells in pathological situations and a prerequisite for efficient nerve repair (Arthur-

Farraj et al 2012, Newbern et al 2011, Woodhoo et al 2009). It is not entirely clear how the

bacterium disseminates through the body, though it probably involves its transmission to

migratory macrophages (Masaki et al 2013) recruited by Schwann cell-derived

chemokines/cytokines (Martini et al 2008).

Demyelinating diseases associated with neuroinflammation

The single nucleotide polymorphisms (SNPs) predisposing humans to susceptibility to multiple

sclerosis are linked to immune-related rather than myelin genes (Nischwitz et al 2011).

However, neurological disability is a consequence of demyelination and axonal degeneration.

Pathological-appearing axons in demyelinating multiple sclerosis lesions (Ferguson et al 1997,

Trapp et al 1998) are commonly associated with activated microglia, macrophages, and

lymphocytes (Ransohoff & Engelhardt 2012), which are frequently considered a driving force

of demyelination and axonopathy (Barrette et al 2013). Importantly, this concept has been

supported independently in a genetically defined mouse model of PMD. Here, the experimental

ablation of the glycolipid-receptor sialoadhesin/Siglec1 (expressed on CD11b-positive

macrophages) (Ip et al 2007) or of mature lymphocytes (Ip et al 2006) alleviated disease

progression. Immune-mediated injury to the CNS can thus be very significant.

Similar to the CNS in multiple sclerosis, peripheral nerves are also frequently affected by

neuroinflammation and demyelination-dependent pain, morbidity, and mortality in Guillain-

Barré syndome and chronic inflammatory demyelinating polyneuropathy. While auto-

antibodies directed against gangliosides or paranodal proteins are frequently observed and

considered pathogenic (Chavada & Willison 2012), it has been difficult to develop efficient

therapy concepts (Meyer zu Horste et al 2007).

Consequently, most of the current medications for demyelinating disease patients target the

immune system. They thus prevent further damage rather than promoting the remyelination

of demyelinated lesions, which appears as a prerequisite for functional repair. It was therefore

important that unbiased, systematic screening towards functional recovery has identified

antagonists of muscarinergic receptors to enhance OPC differentiation and myelination

(Deshmukh et al 2013). Though the actual drug (Benztropine) has many unwanted side

affects, future derivatives and the principal screening strategy provide hope for therapeutic

benefits. Another systematic screening approach has revealed that the coagulation cascade

has pathophysiological relevance in multiple sclerosis (Han et al 2008), providing another

unexpected route to therapeutic attempts.

 
   19  

The development of new drugs that can preserve tissue and promote remyelination will

necessitate considering the intercellular interactions in the pathological CNS, which today

appear much more complex than long anticipated. For example, oligodendrocytes are not

only passively affected by degeneration but play an active part in pathological cascades (Zeis

& Schaeren-Wiemers 2008), immune cells may be recruited by degenerating axons or myelin

or astrocytes (Skripuletz et al 2013), and immune activation may be detrimental, beneficial

or neutral (Aguzzi et al 2013, Sierra et al 2013). Interestingly, particular myelin proteins,

including CD47, can modulate the clearance of myelin debris in the CNS (Gitik et al 2011),

which is a comparatively slow process but beneficial for remyelination (Kotter et al 2006).

Importantly, the order of pathogenic events leading to demyelination, axonopathy,

neuroinflammation, and lymphocyte recruitment probably differs between distinct models

and diseases.

(6) MYELIN PLASTICITY AND AGEING

Oligodendroglial heterogeneity

Oligodendrocytes and myelin have long been viewed as rather homogenous structures.

However, oligodendrocytes display regional heterogeneity, at least with respect to

morphological and electrical properties (Bakiri et al 2011, Chong et al 2012).

Oligodendrocytes derived from dorsal- or ventral-born OPCs (Kessaris et al 2006) myelinate

different brain regions (Tripathi et al 2011), which specifies differences between them in a

partly cell-autonomous manner (Vigano et al 2013). However, ventral- and dorsal-derived

OPCs can replace each other when the respective other population is experimentally depleted

(Kessaris et al 2006). This functional redundancy of OPCs may argue against major

intrinsically specified functional differences (Zuchero & Barres 2013). Instead,

oligodendroglial heterogeneity may emerge in response to the local environment, including

axonal surface cues (Almeida et al 2011), neurotransmitter release (Kolodziejczyk et al

2010), and electrical activity (Wake et al 2011). Together, the capacity of myelinating cells

to react to local cues appears as a prerequisite to refine their functions for axonal activity

and integrity in response to actual requirements.

Oligodendroglial plasticity

The two-dimensional nature of electron micrographs (Figure 1) has also contributed to the

traditional belief that myelin, once developmentally synthesized, is rather static. Indeed the

incorporation of novel myelin membranes into mature myelin is comparatively slow, both in

 
   20  

the PNS (Gould 1977) and the CNS (Colman et al 1982). However, OPCs continue to

proliferate and differentiate, and myelin is slowly but continuously remodeled in healthy adult

mice, generating shorter myelin sheaths but more internodes per oligodendrocyte (Lasiene et

al 2009, Young et al 2013). In humans, the ratio between the volume of the heavily

myelinated white matter and the cortex increases well into adulthood (Tamnes et al 2010).

Importantly, the extent and plasticity of myelination in human brains can be triggered by

external stimuli, including reading, piano practicing, and juggling (Bengtsson et al 2005,

Keller & Just 2009, Liu et al 2012, Scholz et al 2009). Also in adult rodents, the training of

even simple motor tasks stimulates myelination region-dependently (Sampaio-Baptista et al

2013). Remarkably, social isolation negatively impacts myelination in both pubescent

(Makinodan et al 2012) and adult (Liu et al 2012) mice, notwithstanding that it is yet

speculative which molecular cascades may lead from activity or isolation to epigenetic

changes in oligodendrocytes and the expression of myelin genes. Together, myelination is not

only a prerequisite for normal activity but at the same time a consequence thereof.

Impaired myelin integrity has been observed in psychiatric disorders including schizophrenia

and depression (Edgar & Sibille 2012, Fields 2008, Roussos & Haroutunian 2014), opening

the thought-provoking debate whether myelin changes are cause or consequence of mental

decline, or both. Remarkably, myelin is even affected by normal ageing, including decreased

abundance and dynamics, the emergence of redundant myelin profiles, and molecular

alterations affecting distinct myelin proteins (Lasiene et al 2009, Peters 2002, Sturrock

1976), including CNP. Notably, changes affecting CNP are not only a hallmark of myelin

impairments. Indeed, a diminished abundance of CNP is causative of impaired nervous system

functions in both humans and experimental mice, at least when in conjunction with a ‘second

hit‘ such as mental decline or ageing (Hagemeyer et al 2012). In either species,

consequences of CNP-diminishment include the symptoms of depression and catatonia (i.e.

to physically remain in sometimes-bizarre postures). Together, this indicates that alterations

affecting myelin in ageing, which at first glance may appear moderate, indeed represent a key

phase in a vicious cycle of myelin impairments and declining mental and motor capabilities.

We therefore believe that the motor-sensory and cognitive challenges of a socially and

otherwise active lifestyle can contribute to counteracting negative effects of normal ageing

for myelin, and thus for a life-long healthy nervous system.

 
   21  

Acronyms and definitions (glossary)

Remyelination
Myelination of demyelinated axons in the mature CNS

Myelin thickness
Indirect measure of the number of myelin layers, commonly determined by dividing the
axonal diameter by the diameter of the axon including its myelin sheath (g-ratio)

Redundant myelin
Focal outfoldings of complete myelin sheaths, while the number of myelin layers is adequate
for the axonal size. Frequently observed in the biogenesis, pathology, or ageing of myelin

Schwann cell
The myelinating cell of the peripheral nervous system (PNS)

Oligodendrocyte
The myelinating cell of the central nervous system (CNS)

CMT
Charcot-Marie-Tooth disease. Umbrella term for inherited disorders of the PNS
(neuropathies), which are genetically and clinically heterogeneous. Affects about 1 in 2.500
people

Leukodystrophies
Umbrella term for heritable disorders primarily affecting the physiology of the white matter in
the CNS, often involving myelin biogenesis or maintenance. Genetically, pathophysiologically
and clinically heterogeneous, leukodystrophies cumulatively affect about 1 in 10.000 people

Node of Ranvier
The short unmyelinated segment of a myelinated axon at which ion channels are clustered

Internode
The segment of a myelinated axon between two nodes of Ranvier

OPC
Oligodendrocyte progenitor cells; often identified by their immunopositivity for
oligodendrocyte lineage transcription factors (Olig1/Olig2) or the chondroitin sulfate
proteoglycyan (NG2/Cspg4)

MCT
Monocarboxylate transporter

NRG
Neuregulin

GPCR
G-protein coupled receptor

Fyn
A member of the Src family of protein-tyrosine kinases

PLP

 
   22  

Proteolipid protein; a cholesterol-associated tetraspan-transmembrane protein; the dominant

protein of CNS myelin

P0
Myelin protein zero, an Ig-CAM; the dominant protein of PNS myelin

MBP
Myelin basic protein

BACE1
Beta-site amyloid precursor protein-cleaving enzyme 1

TACE/ADAM17
Tumor necrosis factor alpha-converting enzyme / A disintegrin and metalloprotease 17

PMD
Pelizaeus-Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations
affecting the PLP1-gene encoding the major myelin protein PLP

NAA
N-acetylaspartate

Summary points
1. The evolutionary benefit of myelin is rapid nerve conduction
2. Myelin is required for normal motor, sensory, and cognitive abilities
3. Our understanding of the mechanisms of developmental myelination has improved through
in vivo time-lapse imaging and serial block-face electron microscopy
4. An intimate network of interactions exists between myelinating cells, neurons, astrocytes,
and microglial cells; Myelinated axons depend on support by myelinating cells
5. Small metabolites are exchanged between axons and myelinating cells
6. Myelination can be a mechanism of brain plasticity in adulthood
7. Motor, sensory, and social activity may counteract age-dependent myelin impairment
8. The evolutionary cost of myelin is vulnerability to myelin-related disorders

Acknowledgements
We dedicate this article to the memory of Marie Filbin to appreciate her pioneering work on
the molecular functions of myelin proteins in the intercellular interactions of myelinating cells.
H.W. is supported by the Deutsche Forschungsgemeinschaft (DFG WE 2720/2-1). K.-A.N.
holds an European Research Council (ERC) advanced investigator grant. We thank W. Möbius
for the electron micrographs in Figure 1, J. Ficner for support with graphics, and members of
our department for discussions. We apologize to the scientific community for all publications
that we were unable to discuss here because of space restrictions.

 
   23  

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Annotated references

Young / Richardson et al., 2013

In normal mice, new myelin sheaths form by newly generated oligodendrocytes throughout
life.

Werner / Nave et al., 2013

PLP and its homolog GPM6B function partly redundant in CNS myelination.

Snaidero / Simons et al., 2013

CNS myelin biogenesis analyzed by modern microscopy tools.

Hughes / Bergles et al., 2013

OPCs in adult brains are dynamic; they constantly migrate and extend and retract their
processes.

Liu / Casaccia et al., 2012

The social environment can modulate myelin plasticity in adult mice via chromatin
remodeling.

Chong / Chan et al., 2012

Employing myelin-associated inhibitors, neighboring myelin segments segregate laterally to
compete for axonal surface.

Harris / Attwell 2012

Theoretical energy balance of a model white matter tract suggests that having myelin does
not save energy.

Ruckh / Franklin et al., 2012

Blood-derived macrophages can override the remyelination-hostile environment of
demyelinating CNS lesions.

Fünfschilling / Nave et al., 2012

Mature oligodendrocytes support axonal integrity with lactate while oligodendroglial
mitochondria are dispensable for this function.

Wilson / Hartline, 2011

Vertebrate myelin is of glial origin but its functional equivalent in copepods is a neuronal
specialization, exemplifying convergent evolution.

 
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Figure legends

Figure 1. Myelinated axons in the peripheral and central nervous system. A, By electron
microscopy of the peripheral sciatic nerve, a myelinating Schwann cell elaborates myelin as
multiple periodic membrane layers ensheathing an axon. On the same image, a non-
myelinating (Remak-type) Schwann cell engulfs multiple axons of a diameter below 1 µm. B,
In the central optic nerve, oligodendrocytes myelinate multiple axons.

Figure 2. Schematic model of the differentiation of a committed oligodendrocyte progenitor

cell (OPC) into a mature, myelinating oligodendrocyte (OL). OPCs extend and retract cellular
processes until initial contacts are stabilized. The cellular and molecular aspects of myelin
biogenesis are discussed in sections 2-3. In the lower half of the figure, the myelin sheath is
imagined as ‘unrolled‘ for visualization.

Figure 3. Hypothetical model of the metabolic interactions between glial cells and
myelinated axons in the central nervous system. For details, please see section 4.

Table 1 Relative abundance of dominant myelin proteins by quantitative mass spectrometry

Myelin protein, PNS CNS Function, Associated disorder
gene myelin a myelin b Localization
Myelin protein zero, 21% nd Ig-CAM, Charcot-Marie-Tooth neuropathy
P0, Mpz Compact myelin
Proteolipid protein, 0.2% 17% Lipid-associated Hypomyelinating leukodystrophy;
Plp1 tetraspan, Spastic paraplegia type 2
Compact myelin
Periaxin, Prx 16% nd Scaffolding, Charcot-Marie-Tooth neuropathy
Abaxonal layer
between Cajal bands
Myelin basic protein, 8% 8% Adhesion, 18q deletion syndrome
Mbp Compact myelin
Cyclic nucleotide 0.5% 4% 2’,3’-cAMP Catatonia-depression syndrome
phosphodiesterase, metabolism, upon aging
Cnp Non-compact myelin
Myelin nd 1% Ig-CAM, Narcolepsy
oligodendrocyte Abaxonal layer
glycoprotein, Mog
Myelin-associated 0.3% 1% Ig-CAM, Autoantibody-mediated
glycoprotein, Mag Non-compact myelin neuropathy
Sirtuin 2, Sirt2 nd 1% Protein deacetylase,
Non-compact myelin
Claudin 11, Cldn11 nd 1% Tight junction,
Radial component
Fatty acid synthase, 1% nd Lipid metabolism,
Fasn Unknown
Band 4.1-like 1% nd Scaffolding,
protein G, Epb4.1l2 Non-compact myelin
Others 52% 67%
aAccording to Jahn et al., 2009

bAccording to Patzig et al., 2011

 
 Nave & Werner, Figure 1

A PNS B CNS
Cajal
band

Adaxonal
Remak-type myelin
Schwann cell Compact
myelin

Axon
Non- Axon
myelinated
axon
Compact
myelin 1 µm 1 µm

C PNS D PNS E CNS F G

Schwann cell

Compact
myelin Oligodendrocyte

Axon
SLI Radial Compact
Radial
IPL comp. myelin
Non-compact component
MDL myelin

Adaxonal SLI
myelin Adaxonal
myelin
(inner tongue)
Axon

100 nm 500 nm 100 nm

H Nav1.6 MAG DAPI Node

Node
Schmidt-Lanterman incisures
Nucleus

100 µm
 Nave & Werner, Figure 2

Axon

Channel Node
clustering

OPC

Mature
oligodendrocyte

mbp mRNA
Membrane trafficking,
OPC-axon trafficking translation
synapse

Axon

Compact
Incisure myelin

Glia-axonal Axon Contact Lateral and Compaction Maturation,

contact and segment stabilization; radial expansion incisure
retraction selection polarization (‘Wrapping‘) closure

Myelination
 Nave & Werner, Figure 3

A
Capillary

B Oligodendrocyte
Astrocyte
D

Axon C
F E G H I

Pre- Post Internode Node of

Synapse Ranvier

A Glucose B C
Glucose Glutamine
Glycogen
GLUT1 Glycolysis Lactate?
ATP
Pyrurate

Lactate Glutamate

D E F Lactate
Pyruvate/Lactate
Gap junction MCT1
Pyrurate
Metabolites MCT2 ATP

Acetyl CoA TCA

G Myelin lipids H I
Acetate Neurotrophic MVB /
Aspartate ASPA factors Exosomes

Acetyl CoA NAT8L

+Aspartate NAA
Aralar

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