The Initial Myelination in the Central Nervous System

Abstract

Myelination contributes not only to the rapid nerve conduction but also to axonal insulation and protection. In the central nervous system (CNS), the initial myelination features a multistep process where oligodendrocyte precursor cells undergo proliferation and migration before differentiating into mature oligodendrocytes. Mature oligodendrocytes then extend processes and wrap around axons to form the multilayered myelin sheath. These steps are tightly regulated by various cellular and molecular mechanisms, such as transcription factors (Olig family, Sox family), growth factors (PDGF, BDNF, FGF-2, IGF), chemokines/cytokines (TGF-β, IL-1β, TNFα, IL-6, IFN-γ), hormones (T3), axonal signals (PSA-NCAM, L1-CAM, LINGO-1, neural activity), and intracellular signaling pathways (Wnt/β-catenin, PI3 K/AKT/mTOR, ERK/MAPK). However, the fundamental mechanisms for initial myelination are yet to be fully elucidated. Identifying pivotal mechanisms for myelination onset, development, and repair will become the focus of future studies. This review focuses on the current understanding of how CNS myelination is initiated and also the regulatory mechanisms underlying the process.

Full text

The Initial Myelination in the Central
Nervous System
Qiang Yu
1
, Teng Guan
1
, Ying Guo
1,2
, and Jiming Kong
1
Abstract
Myelination contributes not only to the rapid nerve conduction but also to axonal insulation and protection. In the central
nervous system (CNS), the initial myelination features a multistep process where oligodendrocyte precursor cells undergo
proliferation and migration before differentiating into mature oligodendrocytes. Mature oligodendrocytes then extend pro-
cesses and wrap around axons to form the multilayered myelin sheath. These steps are tightly regulated by various cellular
and molecular mechanisms, such as transcription factors (Olig family, Sox family), growth factors (PDGF, BDNF, FGF-2, IGF),
chemokines/cytokines (TGF-β, IL-1β, TNFα, IL-6, IFN-γ), hormones (T3), axonal signals (PSA-NCAM, L1-CAM, LINGO-1,
neural activity), and intracellular signaling pathways (Wnt/β-catenin, PI3 K/AKT/mTOR, ERK/MAPK). However, the fundamen-
tal mechanisms for initial myelination are yet to be fully elucidated. Identifying pivotal mechanisms for myelination onset, devel-
opment, and repair will become the focus of future studies. This review focuses on the current understanding of how CNS
myelination is initiated and also the regulatory mechanisms underlying the process.
Keywords
central nervous system, development, myelin sheath, microglia, oligodendrocyte
Received December 22, 2022; Revised January 31, 2023; Accepted for publication February 16, 2023
Introduction
Myelination is a well-coordinated program that generates
myelin sheaths to wrap around axons. The ensheathment
of axons results in an increased membrane resistance, a
decreased membrane capacitance, and a specific molecular
organization at the nodes of Ranvier (nodes, paranodes,
and juxtaparanodes), thereby significantly facilitating a
rapid saltatory impulse propagation along with the axons
(Coman et al., 2006; Nave & Werner, 2014). As a result,
action potentials can conduct along with myelinated axons
up to 100-fold faster than unmyelinated ones with similar
diameters (Monje, 2018). Apart from its role in speeding
up nerve conduction, myelin also provides trophic axonal
support by transferring pyruvate/lactate through monocar-
boxylate transporters (Philips & Rothstein, 2017), especially
for longer axons whose segments are far (many centimeters
or even meters in humans) away from the cell body but adja-
cent to local glia cells. Moreover, myelin also regulates
axonal transport, the process whereby substances (such as
organelles) are transferred between the cell body and the
axon tip (Edgar & Garbern, 2004). Hence, central nervous
system (CNS) myelination significantly benefits motor,
sensory, and cognitive functions of the brain due to its
essential roles in increasing the speed of action potential
conduction and neuronal homeostasis.
In the CNS, the myelin sheath is formed as a multilamellar
membrane structure by oligodendrocytes (OLs) (Nave &
Werner, 2014; Simons & Nave, 2015), which occurs as a mul-
tistep process during development. These steps include oligo-
dendrocyte precursor cell (OPC) proliferation, OPC migration,
OPC differentiation, subsequent wrapping, and myelin com-
paction (Barateiro et al., 2016). Each step is efficiently orches-
trated by both cellular and extracellular factors. However, the
fundamental mechanism regulating initial myelination is
not fully understood. Failure of CNS myelination would
eventually lead to neurologic and neurodegenerative dis-
eases, such as leukodystrophies (Kolodny, 1993). Hence,
a comprehensive understanding of physiological behaviors
1
Department of Human Anatomy and Cell Science, University of Manitoba,
Winnipeg, Manitoba, Canada
2
Department of Forensic Medicine, Hebei North University, Zhangjiakou,
Hebei, China
Corresponding Author:
Jiming Kong, Department of Human Anatomy and Cell Science, University of
Manitoba, Winnipeg, Manitoba, Canada R3E 0J9.
Email: jiming.kong@umanitoba.ca
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of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-
us/nam/open-access-at-sage).
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in CNS myelination is required to identify potential therapeutic
targets in pathological conditions.
In this review, we first summarize the key processes of
initial myelination. Next, we highlight current progress in
our understanding of mechanisms of initial CNS myelination
from the aspects of transcription factors, extracellular factors,
axonal regulation, and signaling pathways. Finally, we
compare initial myelination with remyelination before con-
cluding the review with open questions in this field.
Initial Events of CNS Myelination
OL Lineage Development
The maturation of OLs is a prerequisite for myelin sheath for-
mation, highlighting the importance of OL lineage develop-
ment for myelination. Generally, the OL lineage development
can be divided into four stages, OPCs, late OPCs, immature
(or premyelinating) OLs, and mature (or myelinating) OLs,
which are characterized by the morphological changes and dif-
ferent expression patterns of specific markers (Figure 1)
(Barateiro & Fernandes, 2014).
Inthemousebrain,OPCsarefirst observed in the ven-
tricular germinal layer of the lateral basal plate of the dien-
cephalon at around embryonic day (E) 9 (Timsit et al., 1995).
Interestingly, in the forebrain, a study describes three distinct
waves of OPCs in a ventral-to-dorsal progression (Kessaris
et al., 2006). Specifically, the first wave of OPCs originates
in the ventral forebrain at E12.5, followed by a second wave
of OPCs from the lateral and/or caudal ganglionic eminences
at around E14.5. Finally, a third wave of OPCs occurs within
the postnatal cortex. OPCs are proliferative cells with highly
migratory capabilities, allowing them to migrate along with vas-
culature (Tsai et al., 2016) to the whole CNS before maturation
and myelination. Unlike neurons that proliferate and migrate in
the embryonic stage, these two processes in OPCs occur mainly
in postnatal phases in rodents (Snaidero & Simons, 2014). At
about postnatal day (P) 2, late OPCs account for the majority
of OL lineage cells, with a small amount of immature OLs
existing. Mature OLs appear at P7 to initiate the CNS mye-
lination (Figure 2), which is almost completed in most brain
regions by P60 (Snaidero & Simons, 2014). In adults, OPCs
and intermediately differentiated OLs are present across the
entire CNS (Dawson et al., 2003). Of note, CNS myelina-
tion follows a specific time course and sequence rather
than occurring simultaneously. Generally, in mammals,
CNS myelination starts in the brainstem and then continues
rostrally to the forebrain and caudally to the spinal cord.
This pattern correlates very closely with developmental
milestones (Dietrich et al., 1988). For instance, myelination
occurs early from motor-sensory roots, special senses, and
the brainstem (Kinney et al., 1988), which are the necessary
structures for reflex behaviors and survival.
Compared with rodents, only a few studies have addressed
the OLs lineage in humans. OPCs in humans are first observed
in the forebrain at 10 gestational weeks (g.w.). Immature OLs are
observed between 18 and 28 g.w., although OPCs and late OPCs
are still the major cell types during this stage (Barateiro et al.,
2016). Thus, OLs lineage development during 18–28 g.w. of
humans is similar to that of rodents at P2. Myelin basic
protein (MBP) positive OLs are initially observed at around
28 g.w. during human development (Back et al., 2001;
Barateiro et al., 2016; Hüppi et al., 1998), resembling the
time point of P7 in rodents (Figure 2).
In zebrafish, another broadly used model for myelination
study, OPCs are initially observed as early as 36 h post fertili-
zation (hpf) (Kirby et al., 2006) and MBP, a marker of mature
Figure 1. Oligodendrocyte Lineage Development and Specific
Markers in Each Stage (mammals). OPCs, oligodendrocyte
precursor cells. OLs, oligodendrocyte. PDGFRα, platelet-derived
growth factor receptor α. CNPase, 2′,3′-cyclic nucleotide
3′-phosphodiesterase. GalC, galactocerebroside C. MAG, myelin
associated glycoprotein. MBP, myelin basic protein. MOG, myelin
oligodendrocyte glycoprotein. PLP, proteolipid protein.
Figure 2. Timeline of CNS Myelination Development in Humans,
Rodents, and Zebrafish. The green box indicates the time of OPCs
appearance. The orange box indicates the stage where OPCs and
pre-myelinating OLs exist. The blue box indicates the time of
myelination onset. g.w.=gestational weeks. E =embryonic day.
OPCs, oligodendrocyte precursor cells. OLs, oligodendrocyte. hpf,
hours post fertilization. dpf, days post fertilization. CNS, central
nervous system.
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myelin, appears at about 60 hpf (Figure 2) (Almeida et al.,
2011). Generally, CNS myelination is structurally and func-
tionally conserved between zebrafish and mammals, although
differences regarding the composition of myelin proteins are
noticed (Figure 3) (Gargareta et al., 2022; Jahn et al., 2020;
Siems et al., 2021). For example, myelin protein zero, a
protein only found in the peripheral nervous system (PNS)
of mammals, is present in the CNS of zebrafish (Brösamle
& Halpern, 2002). Besides, zebrafish myelin also expresses
some proteins that are absent in mammals, such as claudin K
(Münzel et al., 2012), 36 K (Morris et al., 2004), and
Zwilling-A/B (Schaefer & Brösamle, 2009). Moreover, a
recent study shows that CD59 is the fourth most abundant
(4.6%) myelin protein in zebrafish (Siems et al., 2021),
while its abundance in mammals is comparatively low
(0.01%) (Gargareta et al., 2022). Hence, more studies are
required to explain the differences and determine the
precise role of different myelin proteins in both zebrafish
and mammals.
Axon Targeting, Contact, and Process Polarization
After ceasing migration, OPCs undergo continual process
extension until making stable contact with the axonal mem-
brane, subsequently forming an axon–glial interaction domain
for further communication, namely, branching (Figure 4).
How OLs precisely target axons during initial myelination
remain largely unknown. A recent study suggests that axon
caliber alone, in the absence of axonal signals, allows myelina-
tion to initiate (Mayoral et al., 2018). Moreover, a study shows
that OLs can sense the diameter of microfibers in vitro, thereby
increasing sheath length with larger fibers (Bechler et al.,
2015). These results are in line with the fact that nearly all
axons with a diameter greater than 0.2 μm are myelinated
(Goebbels et al., 2017), indicating an important role of
axonal biophysical properties in axon selection during
myelination. Presumably, this may involve a curvature-
dependent mechanism, such as regulations of certain
membrane-anchored proteins (Chang-Ileto et al., 2011;
McMahon & Boucrot, 2015). Interestingly, similar to the
“growth cone”model in axon outgrowth and pathfinding, a
growing body of evidence also suggests that OLs processes
extend or retract following permissive or repulsive cues on
axons, respectively. In rodents, such permissive cues include
laminin-2/merosin, EphA4/B1, L1-CAM, N-cadherin, and
Netrin-1 (Figure 4) (Thomason et al., 2020). The negative/
repulsive cues include axonal ephrin-A1/B2, PSA-NCAM,
LINGO-1, Jam2, and Galectin-4 (Sherman & Brophy, 2005;
Thomason et al., 2020). However, none of these cues are suffi-
cient to instruct OLs to target axons in the CNS, which requires
further research for a better understanding of this.
Interestingly, recent studies also support the role of neural
activity in regulating axon targeting during initial myelination.
For example, blocking action potentials in the zebrafish spinal
cord results in axonal mistargeting and hypomyelination
(Hines et al., 2015). However, some in vitro studies show
that OLs can also myelinate paraformaldehyde (PFA)-fixed
axons (Rosenberg et al., 2008) and nanofibers (Lee et al.,
2013) in the absence of neural activity. Likely, correct
axonal targeting depends on multiple cues, including both
neural activity and OL-intrinsic signals.
After an initial axon–glia contact, a series of changes in
OLs occur, including the downregulation of RhoA activity
(Baer et al., 2009) and the local enrichment of phospholipid
in OL membranes, such as PIP2 and PIP3 (Goebbels et al.,
2010; Snaidero et al., 2014), eventually leading to a polariza-
tion of myelinating cells toward axons.
Myelin Wrapping
Once contact is formed and the polarization is finished, the
wrapping process initiates. In the CNS, individual OL can
Figure 3. Relative Abundance of CNS Myelin Proteins in Humans (Jahn et al., 2020), Rodents (Gargareta et al., 2022), and Zebrafish (Siems
et al., 2021). OPCs, oligodendrocyte precursor cells. OLs, oligodendrocyte. CNP, CNPase, 2′,3′-cyclic nucleotide 3′-phosphodiesterase.
MAG, myelin-associated glycoprotein. MBP, myelin basic protein. MOG, myelin oligodendrocyte glycoprotein. PLP, proteolipid protein. MPZ,
myelin protein zero. CLDNK, claudin K. CNS, central nervous system.
Yu et al. 3

myelinate up to 50 axons (Baumann & Pham-Dinh, 2001), with
the number of membrane layers in one axon reaching up to 160
(Hildebrand et al., 1993). Nevertheless, the exact geometry of
myelin wrapping is challenging to document due to the limita-
tion of imaging technologies. Previously, two wrapping models
are proposed, namely the “carpet crawler”model and the
“yo-yo”model (Figure 5). The “carpet crawler”model suggests
that, after axon–glia contact formation, the leading edge of the
OLs membrane spreads and flattens into a broadsheet and then
moves underneath itself to form the mature myelin sheath
(Bunge et al., 1961). Alternatively, the “yo-yo”model pro-
poses that the OL processes wrap around the axons until an
appropriate number of layers are formed, then extend laterally
into overlapping sheets (Pedraza et al., 2009). However,
neither of these models provides the mechanisms of how syn-
thesized molecules go through the compact myelin and reach
the innermost layer, which cannot be easy as the inner layers
become more and more distant to neural somas as the wrapping
proceeds. With the advancement of imaging technologies,
better visualization and understanding regarding the wrapping
model are gained. By taking advantage of three-dimensional
electron microscopy (3D EM), a newer model is proposed:
the triangle-shaped leading edge moves underneath previously
deposited layers, followed by lateral extension of each layer of
myelin (Snaidero et al., 2014). This wrapping model allows
close contact between each myelin layer and its underlying
axon, thereby contributing to axon–glia communication.
Notably, the authors also suggest that cytoplasmic channels
appear transiently within compact myelin to provide a short
connection between the outer and inner tongue, allowing the
transportation of newly synthesized membrane components
from the soma to the inner tongue. As myelination completes,
these cytoplasmic channels resolve (Snaidero et al., 2014).
The molecular mechanisms of the wrapping process have
also become a focus of many studies. Of note, OLs show a peri-
odic actin pattern that is not seen in astrocytes or microglia,
Figure 4. Schematic of Myelination Progression in Mammals. After migrating to the final spot, OPCs extend or retract processes following
attractive or repulsive cues on axons. OPC, oligodendrocyte precursor cell. OL, oligodendrocyte.
Figure 5. Schematic of Different Wrapping Models Proposed. The “carpet crawler”model proposes that the process flattens into a broad
sheet before wrapping. The “yo-yo”model suggests that the OL processes wrap around the axons until an appropriate number of layers are
formed, then extend laterally into overlapping sheets. The current model suggests that the triangle-shaped leading edge moves underneath
previously deposited layers, followed by lateral extension of each layer of myelin.
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indicating tight cytoskeletal regulation during myelination
(Brown & Macklin, 2019). In addition, one study indicates
that actin polymerization in the leading edge is the main
force driving the wrapping process, while actin depolymeriza-
tion promotes membrane spreading by reducing surface tension
(Nawaz et al., 2015). This is in line with another model propos-
ing that actin polymerization powers OLs process extension in
an Arp2/3-dependent manner, while actin depolymerization
drives myelin wrapping (Zuchero et al., 2015). In this model,
MBP prevents the actin disassembly factors cofilin and gelsolin
from binding to PIP2, resulting in a release of cofilin/gelsolin to
disassemble actin, thereby driving myelin wrapping.
Myelin Compaction
Myelin compaction coincides with wrapping. Initially, myelin
membranes are negatively charged due to the abundance of
phospholipids (PIP2, PIP3). Therefore, a mechanism of neu-
tralizing these negative charges and pulling adjacent layers
together is needed for compaction, which is now recognized
as the key role of MBP. MBP shows a high affinity to nega-
tively charged phospholipids, such as PIP2, thereby function-
ing as a “zipper”by pulling together two bilayers. Mice with
MBP gene mutation (shiverer mice) fail to form compact
myelin, resulting in severe dysmyelination with a characteris-
tic “shivering”symptom (Readhead & Hood, 1990).
Of note, Snaidero et al. (2014) demonstrate that there is a
delay of two or three wraps behind the growing tip during com-
paction, which makes room for newly formed layers. In this
study, knockout of 2′,3′-Cyclic nucleotide 3′-phosphodiesterase
(CNP), the third most abundant protein in CNS myelin in
humans and rodents (Figure 3), results in a reduction of uncom-
pacted wraps within the myelin sheath, indicating a potential
role of CNP in preventing the myelin compaction in the inner-
most regions. It is likely that the leading edge grows together
with the accumulation of CNP, while MBP appears two or
three wraps behind to initiate myelin compaction. Therefore,
proper myelin compaction may require equilibrium between
MBP and CNP.
Regulation of the Initial CNS Myelination
Transcription Factors
OL lineage development and myelination are under tight tran-
scriptional control (Figure 6). The Olig family is one of the
most studied transcriptional regulators for CNS myelination.
Olig2 is required during OPCs specification and maintenance,
as exemplified by the loss of OPCs in Olig2 null mice (Ligon
et al., 2006; Lu et al., 2002). In addition, Olig2 also plays a
prominent role in promoting OPCs migration and OLs dif-
ferentiation (Maire et al., 2010; Wegener et al., 2015; Zhu
et al., 2012). Therefore, Olig2 is considered a master tran-
scriptional regulator for most stages of OL lineage develop-
ment, from OPCs specification to myelin protein production
(Zhang et al., 2022). In contrast, Olig1 seems to be more
involved in OLs maturation. For example, Olig1 null mice
exhibit severer dysmyelination due to the loss of mature/
myelinating OLs, eventually leading to death within the third
postnatal day (Xin et al., 2005). However, a subsequent
study using new Olig1 knockout mice models shows that
Olig1 null mice only exhibit a delay of OL differentiation
but do not develop long-term myelin deficits (Paes de Faria
et al., 2014), indicating a nonessential role of Olig1 in OL
development. The possible reasons for the conflicting results
may lie in how the mice lines were generated in these two
studies. Paes de Faria et al. generated two independent Olig1
null mice models by different methods—one by homologous
recombination in mouse embryonic stem cells, and the other
one by transgenic rescue of an Olig1/Olig2 double-null mice
line. Both lines showed consistent results. In contrast, Xin
et al. crossed Olig1 null mice (with a Cre-Pgk-Neo cassette
at the Olig1 locus) with FLP-expressing mice to remove the
Pgk-Neo, which could potentially affect Olig2 expression con-
sidering that Olig1 and Olig2 locate close to each other. In
zebrafish, both Olig1 and Olig2 are reported to control OL dif-
ferentiation (Li et al., 2007; Park et al., 2002), indicating the
similar role of the Olig family in regulating OL development.
The Sox family is another major group of transcriptional
regulators involved in myelination (Figure 6). Sox10 is
required for terminal OLs differentiation, as exemplified by
the complete loss of MBP +and PLP +OLs in Sox 10 null
mice (Stolt et al., 2002). In zebrafish, the in vivo time-lapse
imaging shows that the myelinating OLs in Sox 10 mutants
can initiate axon ensheathment without expressing myelin
proteins but soon die after the onset of myelination (Takada
et al., 2010). This may suggest a more important role of
Sox10 in myelin maintenance than during the onset of myeli-
nation. Like Olig2, some Sox factors, such as Sox8 and Sox9,
are also required for OL specification and differentiation
Figure 6. Schematic of Transcriptional Regulations in Different
Stages of the OL Lineage Development. Arrows (→) indicate
positive regulations, and the symbol (T) represents negative
regulations. OPCs, oligodendrocyte precursor cells. OLs,
oligodendrocyte. TFEB, transcription factor EB.
Yu et al. 5

(Stolt et al., 2003, 2004). In contrast, other Sox members are
found to inhibit OL differentiation by competing with Sox10,
such as Sox5 and Sox6 (Emery & Lu, 2015).
In addition to the two major families of transcriptional reg-
ulators mentioned above, some new factors have been
recently identified. For example, Tcf4 positively regulates
OL differentiation in both myelination and remyelination
without engaging its downstream Wnt/ β-catenin pathway
(Hammond et al., 2015). Tcf4 null mice develop myelin def-
icits due to a lack of mature OLs (Phan et al., 2020). More
recently, an elegant study shows that transcription factor EB
induces selective OLs elimination in normally unmyelinated
brain regions, thereby controlling when and where the
initial myelination occurs (Sun et al., 2018). In addition, the
myelin gene regulatory factor (Mrf) is also proven to crucially
regulate CNS myelination by cooperating with Sox10. Mrf
physically and functionally interacts with Sox10, synergisti-
cally promoting myelin gene expression (Hornig et al.,
2013). Indeed, most transcriptional factors regulate myelina-
tion by directly binding to the promoter regions of myelin
genes, thereby influencing myelin protein (MBP, PLP, and
MAG) production (Tiane et al., 2019).
Extracellular Factors
Many studies have highlighted the importance of some
growth factors in CNS myelination. Notably, many of them
are released by astrocytes and microglia, the other two
major glial cell types in the CNS (Figure 7). As an example
of astrocyte-derived factors, the platelet-derived growth
factor-alpha significantly promotes OPC proliferation while
inhibiting its maturation (Traiffort et al., 2020). This is consid-
ered an important mechanism for maintaining the OPC pool
and preventing OPCs from premature differentiation (Noble
et al., 1988; Raff et al., 1988). The brain-derived neurotrophic
factor (BDNF), derived from astrocytes and neurons (Miranda
et al., 2019), is required for myelin development, as exempli-
fied by the delayed CNS myelination in BDNF null mice
(Cellerino et al., 1997). Moreover, the fibroblast growth
factor 2 (FGF-2), highly expressed in astrocytes (Newman
et al., 2000), is suggested to promote OPCs proliferation
and inhibit their differentiation into mature OLs (Bansal &
Pfeiffer, 1994; McKinnon et al., 1990). In addition, astrocytes
also secrete ciliary neurotrophic factor (CNTF) to benefitOL
maturation through the Janus kinase (JAK) pathway (Stankoff
et al., 2002). Some microglia-derived growth factors are also
reported to regulate myelin development, such as insulin-like
growth factor 1 (IGF-1, also produced by neurons) and insulin-
like growth factor 2 (IGF-2). IGF-1 null mice exhibit reduced
OL survival and maturation, suggesting an important role of
IGF-1 in regulating OL lineage development (Ye et al., 2002).
Interestingly, IGF-1 is expressedintheactivated (ameboid-like)
microglia within the corpus callosum until P7, the time point of
myelination onset. After P7, IGF-1 expression levels decrease
along with the morphological changes of microglia from
ameboidtoramified shape (Traiffort et al., 2020). Therefore,
IGF-1 may play a unique role during the initiation of myelination
rather than after the myelination onset. Besides IGF-1, IGF-2
also promotes OL survival in vitro (Nicholas et al., 2002),
although its role in myelination is less extensively studied.
Interestingly, compared to astrocyte-derived factors,
microglia-derived factors appear to play a more significant
role in OL differentiation and myelination. A study shows
that microglia-conditioned medium, but not astrocyte-
conditioned medium, significantly enhances myelin protein
expression and myelin sheath formation in the neuron-OL
myelination coculture (Pang et al., 2013). However, the funda-
mental mechanism of how microglia regulate myelination
through their secretome remains unclear.
Cytokines and chemokines are also important players in the
regulation of CNS myelination, and most of them are microglia-
derived (Figure 7). Activated microglia secrete TGF-β,IL-1β,
TNF-α, IL-6, and IFN-γto regulate OL development during
development, and a blockade of these factors leads to
impaired oligodendrogenesis (Shigemoto-Mogami et al.,
2014). Specifically, IL-1βenhances OL maturation but nega-
tively regulates OPC proliferation (Vela et al., 2002). In con-
trast, IFN-γpromotes OPC proliferation while inhibiting its
differentiation (Baerwald & Popko, 1998; Chew et al., 2005),
indicating that different microglia-derived cytokines may
have opposite influences on OL development, and they work
synergistically to determine OL fates. Besides microglia, astro-
cytes also produce chemokines to regulate OL development,
such as CXCL-1. CXCL-1 may inhibit OPC migration while
promoting its proliferation (Tsai et al., 2002).
Figure 7. Major Growth Factors, Chemokines and Cytokines
Released from Astrocytes and Microglia During Oligodendrocyte
Lineage Development and Myelination. Arrows (→) indicate positive
regulations, and the symbol (T) represents negative regulations.
OPCs, oligodendrocyte precursor cells. OLs, oligodendrocyte.
PDGF, platelet-derived growth factor. BDNF, brain-derived
neurotrophic factor. CNTF, ciliary neurotrophic factor. IGF,
insulin-like growth factor. FGF-2, fibroblast growth factor 2.
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Hormones, such as thyroid hormone (T3), are also closely
involved in myelination. During early development, brain T3
is of maternal origin via placenta (Morreale de Escobar et al.,
1987). T3 controls OL development in mammals by inhibit-
ing OPC proliferation before promoting OL differentiation
in vitro and in vivo (Almazan et al., 1985; Calza et al.,
2002). Consistently, a lack of T3 in zebrafish results in
hypomyelination, which is restored after T3 supplementation
(Farías-Serratos et al., 2021). This sheds light on a well-
conserved regulation mechanism of CNS myelination between
mammals and zebrafish.
Axonal Regulations
Regarding axonal signaling during initial myelination, one
interesting fact is that OLs can myelinate PFA-fixed axons
and even nanofibers in vitro. This is agreed by a more recent
study showing OLs derived from different areas (cortex and
spinal cord) can myelinate microfibers in vitro with the same
internode length as seen in corresponding regions in vivo
(Bechler et al., 2015). However, there may be other explana-
tions. Alternatively, it is very likely that some inhibitory mol-
ecules expressed on the surface of axons prevent myelination
from happening until neutralized in vivo. Indeed, many studies
have identified various axonal adhesion molecules that negatively
regulate OLs development and myelination. PSA-NCAM and
L1, the best-studied adhesion molecules, are expressed on non-
myelinated axons and are significantly downregulated during
the onset of myelination (Charles et al., 2000; Jakovcevski
et al., 2007). Presumably, these inhibitory adhesion molecules
need to be neutralized before the wrapping process initiates,
although a more direct correlation between these two events
awaits testing. LINGO-1 is another inhibitor of myelination.
In rats, downregulation of LINGO-1 promotes myelination,
and conversely, overexpression of LINGO-1 inhibits myelin
formation by activating RhoA signaling (Mi et al., 2005).
Consistently, LINGO-1 knockdown in zebrafish enhances
OL differentiation and promotes subsequent myelination
(Yin & Hu, 2014). Together, these inhibitory molecules
are closely involved in regulating myelination development,
potentially the onset of myelination. If these inhibitors are
the key factors to control the timing of myelination onset,
some mechanisms must exist to regulate the persistence of
the inhibitory signals during initial myelination, such as
the “inhibitor of the inhibitor.”
In addition to adhesion molecules, neuronal activity is also
suggested to profoundly regulate myelination in vivo.Astudy
shows that pharmacogenetic stimulation of somatosensory
axons in the mouse brain increases OPCs differentiation, result-
ing in thicker myelin in simulated axons compared to neigh-
boring nonsimulated ones (Mitew et al., 2018). Moreover,
using zebrafish, a recent study (Mensch et al., 2015) shows
that a reduction in synaptic vesicle release results in a
decrease in the axon numbers myelinated by one single OL.
Furthermore, when increasing neural activity, 40% more
axons are myelinated by a single OL, indicating an activity-
dependent regulation during myelination. However, even
without neural activity, an individual OL still myelinates
around 60% axons of its full capacity. Therefore, it is reason-
able to believe that neuronal activity is an essential modulator
for myelin sheath development and refinement, although it
may not be required for the ensheathment itself. Indeed, an
emerging consensus nowadays is that the activity-driven mye-
lination plasticity is essentially important for the myelination
maintenance stage, during which learning and exercising
occur frequently. Socially isolated mice develop hypomyelina-
tion in the prefrontal cortex (Liu et al., 2012; Makinodan et al.,
2012). Consistently, an enriched environment increases myeli-
nation in rat corpus callosum (Zhao et al., 2012). Together,
these studies highlight the important role of environmental
input in myelin sheath formation. One can assume that the
results are led by the changes in neuronal activity, although
more straightforward evidence is needed in future studies.
The molecular mechanisms of this activity-dependent
myelination remain unclear. Some studies propose that the
glutamate released from axons may interact with myelinat-
ing OLs since both OPCs and OLs express the AMPA and
NMDA receptors for glutamate (Bakiri et al., 2009; Butt,
2006; Káradóttir & Attwell, 2007). Alternatively, another
study suggests that neuronal activity may control the release
of neuregulin 1 from neural axons, thereby switching OLs
between activity-dependent mode and activity-independent
mode (Lundgaard et al., 2013).
Signaling Pathways
Many highly conserved intracellular signaling pathways, such
as Wnt/β-catenin, PI3 K/AKT/mTOR, and ERK/MAPK sig-
naling pathways, are suggested to tightly regulate CNS mye-
lination. Initially, Wnt signaling is identified as a negative
regulator of OL differentiation and myelination. Activation
of Wnt signaling in mice leads to a delayed appearance of
mature OLs and myelin proteins, while the number of OPCs
remains unchanged (Feigenson et al., 2009), suggesting that
the Wnt pathway is potentially involved in the OL differenti-
ation stage. Similarly, upregulation of Wnt/β-catenin by delet-
ing its antagonist in mice, such as APC and Axin2, results in
impaired OL maturation, subsequently leading to hypomyeli-
nation (Fancy et al., 2011; Lang et al., 2013). However, con-
flicting results are obtained when inhibiting endogenous
β-catenin in the conditional knockout mice. One study dem-
onstrates that the Cre activity-induced β-catenin knockout
does not influence OL differentiation (Lang et al., 2013),
whereas another study shows that the conditional knockout
of β-catenin causes a significant reduction in the numbers of
mature OLs in mice brains from E18 to P15 (Dai et al.,
2014). Of note, the latter study applies tamoxifen to delete
the β-catenin gene much earlier than the former (E10.5
versus P6), potentially leading to conflicting results. Early
loss of β-catenin may have more meaningful influences on
Yu et al. 7

OL development. However, in a zebrafish study, siRNA-induced
knockdown of β-catenin inhibits OL differentiation and myelina-
tion in zebrafish larvae (Tawk et al., 2011), suggesting that the
Wnt signaling pathway may alsohavepromotingeffectson
myelination. Further studies are needed to clarify these seem-
ingly conflicting conclusions.
PI3K/AKT/mTOR is another classic intracellular signal-
ing pathway involved in many basic processes, such as cell
proliferation and survival (Dudek et al., 1997; Franke et al.,
1997). OL development is no exception. Overactivation of
PI3 K/AKT/mTOR results in increased myelin thickness in
mice (Flores et al., 2008; Harrington et al., 2010). Conversely,
the downregulation of mTOR by its inhibitor rapamycin sig-
nificantly impairs myelination in transgenic mice (Narayanan
et al., 2009). Interestingly, in studies using knockout mice,
the spinal cord seems more vulnerable to the deletion of
mTOR than the brain. Mice with mTOR conditional ablation
exhibit nearly unaffected myelination in the corpus callosum,
while the spinal cord, in contrast, shows severe hypomyelina-
tion (Bercury et al., 2014; Wahl et al., 2014). Many studies
show that mTOR deletion causes a reduction in MBP
mRNA and MBP proteins in the spinal cord (Bercury et al.,
2014; Wahl et al., 2014), highlighting the role of mTOR sig-
naling in regulating MBP production at both transcription
and translation levels.
ERK/MAPK is also considered a positive regulator of CNS
myelination. Reduced myelin thickness is observed in Erk1/2
conditional knockout mice (Ishii et al., 2019). Furthermore,
one study identifies the FGF-Receptor-type-2 (FGFR2) as a
key upstream signal of ERK by showing that the myelin thick-
ness reduction induced by conditional ablation of FGFR2 can
be rescued by upregulating ERK signaling in transgenic mice
(Furusho et al., 2017). ERK signaling also regulates adulthood
myelination, as exemplified by the reinitiation of myelin growth
in adult mice following ERK upregulation (Ishii et al., 2016;
Jeffries et al., 2016). More recently, a study points out
that the ERK/MAPK and the PI3 K/AKT/mTOR signaling
pathways need to work both independently and coopera-
tively for a finely tuned myelination (Ishii et al., 2019), sug-
gesting the presence of crosstalk among these key signaling
pathways during myelination.
Some other signaling pathways also contribute to myelin
development. For example, the bone morphogenetic protein
(BMP) pathway is a potent inhibitor of OL differentiation
and myelin protein expression (Grinspan, 2015). When treat-
ing rodent OPCs with BMP4 in vitro, their differentiation is
significantly inhibited in a dose-dependent manner
(Grinspan et al., 2000). Similarly, Notch signaling pathways
are also suggested to inhibit OPCs differentiation during
development (Genoud et al., 2002; Wang et al., 1998).
Remyelination Versus Initial Myelination
Remyelination refers to the adaptive responses to dys- and
demyelination whereby the myelin sheath is structurally and
functionally restored. Many similarities are shared between
initial myelination and remyelination regarding the major
steps and the regulating mechanisms. By analogy with
initial myelination, remyelination starts with the recruitment
of adult OPCs to the lesion sites, followed by morphological
changes of OPCs, OPCs differentiation, wrapping, and
myelin compaction. Both OPCs and adult OPCs proliferate
and migrate to the spot where myelination is needed, although
adult OPCs have a longer basal cell cycle time and slower
migration speed (Wolswijk & Noble, 1989). As seen in
initial myelination, an upregulation of several transcription
factors (Olig2, Sox2) is also observed when remyelination ini-
tiates (Fancy et al., 2004; Shen et al., 2008; Watanabe et al.,
2004). In addition, the inhibitory roles of LINGO-1 and
Wnt signaling can also serve as important regulating mecha-
nisms for remyelination (Fancy et al., 2009; Mi et al., 2007).
However, the differences between initial myelination
and remyelination are documented. First, the relationship
between the caliber of axons and the thickness of myelin
sheath, namely g-ratio, is altered. The optimal g-ratio in
initial myelination is 0.6, while remyelination only gener-
ates a thinner and shorter myelin sheath, resulting in a
greater g-ratio than expected (Blakemore, 1974). Second,
some molecular mechanisms vary between initial myelination
and remyelination. On the one hand, some molecules are
more involved in initial myelination than in remyelination.
For example, a recent study shows that fatty acid–binding
protein 7 (FABP7) is important in OPCs differentiation during
development but not in remyelination (Foerster et al., 2020).
On the other hand, some mechanisms are, at least for now,
remyelination-specific.Forexample,CD47,awell-documented
“don’t eat me signal,”may serve as a key mechanism of remye-
lination failure. CD47 tags myelin debris after demyelination
and functions as a marker of “self,”thereby preventing their
clearance by microglia (Gitik et al., 2011). However, the role
of CD47 in initial myelination has not been addressed yet.
Indeed, since initial myelination and remyelination have simi-
larities but are not identical, it is reasonable that they share
some signaling pathways but also own their unique way of
orchestrating the processes.
Concluding Remarks
Research regarding initial CNS myelination has gained great
progression due to researchers’passion for this field. It is well
recognized that myelination involves many steps regulated in
time and space, during which various molecules and signaling
pathways are responsible for the orchestration.
In this review, we have covered some mechanisms in
initial CNS myelination. However, the picture is incomplete,
with many challenging questions remaining to be answered.
For example, the key signal that triggers the initiation of
CNS myelination remains largely unknown. In contrast, a
large body of evidence has suggested a key mechanism for
PNS myelination. Specifically, the level of neuregulin 1
8ASN Neuro

type III expressed on the PNS axons is a pivotal instructive
cue for myelination. Myelinated axons express significantly
higher levels of neuregulin 1 type III than unmyelinated
ones, resulting in different ensheathment fates of PNS axons
(Taveggia et al., 2005). This explains the fact that Schwann
cells, the myelinating glia cells in the PNS, do not myelinate
the neuregulin 1 type III-deficient nanofibers in vitro (Bechler
et al., 2015). However, such key factors or mechanisms have
yet to be identified in the CNS, which will become a focus in
future studies. Fortunately, a diversity of animal models
(zebrafish) and imaging techniques (3D EM) offer preeminent
tools for in vivo myelination studies. Hopefully, researchers
can take advantage of them to get a deeper insight into not
only initial myelination but also myelin repair after injuries
or demyelinating diseases, thereby helping identify the poten-
tial treatment targets for them.
Acknowledgments
The authors would like to thank China Scholarship Council as it pro-
vides financial support for author Q.Y’s study in Canada.
Author contributions
J.K. selected the topic. Q.Y. wrote the paper; T.G. and Y.G. reviewed
and edited the paper; J.K. critically revised the paper.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: Q.Y. has
received financial support from China Scholarship Council.
ORCID iD
Qiang Yu https://orcid.org/0000-0002-0094-0479
References
Almazan, G., Honegger, P., & Matthieu, J. M. (1985). Triiodothyronine
stimulation of oligodendroglial differentiation and myelination. A
developmental study. Dev Neurosci,7(1), 45–54. https://doi.org/
10.1159/000112275
Almeida, R. G., Czopka, T., Ffrench-Constant, C., & Lyons, D. A.
(2011). Individual axons regulate the myelinating potential of
single oligodendrocytes in vivo. Development,138(20), 4443–
4450. https://doi.org/10.1242/dev.071001
Back, S. A., Luo, N. L., Borenstein, N. S., Levine, J. M., Volpe, J. J.,
& Kinney, H. C. (2001). Late oligodendrocyte progenitors coin-
cide with the developmental window of vulnerability for human
perinatal white matter injury. J Neurosci,21(4), 1302–1312.
https://doi.org/10.1523/jneurosci.21-04-01302.2001
Baer, A. S., Syed, Y. A., Kang, S. U., Mitteregger, D., Vig, R.,
Ffrench-Constant, C., Franklin, R. J., Altmann, F., Lubec, G.,
& Kotter, M. R. (2009). Myelin-mediated inhibition of oligoden-
drocyte precursor differentiation can be overcome by
pharmacological modulation of Fyn-RhoA and protein kinase C
signalling. Brain,132(Pt 2), 465–481. https://doi.org/10.1093/
brain/awn334
Baerwald, K. D., & Popko, B. (1998). Developing and mature oligo-
dendrocytes respond differently to the immune cytokine interferon-
gamma. J Neurosci Res,52(2), 230–239. https://doi.org/10.1002/
(sici)1097-4547(19980415)52:2<230::Aid-jnr11>3.0.Co;2-b
Bakiri, Y., Burzomato, V., Frugier, G., Hamilton, N. B., Káradóttir,
R., & Attwell, D. (2009). Glutamatergic signaling in the brain’s
white matter. Neuroscience,158(1), 266–274. https://doi.org/
10.1016/j.neuroscience.2008.01.015
Bansal, R., & Pfeiffer, S. E. (1994). Inhibition of protein and lipid
sulfation in oligodendrocytes blocks biological responses to
FGF-2 and retards cytoarchitectural maturation, but not develop-
mental lineage progression. Dev Biol,162(2), 511–524. https://
doi.org/10.1006/dbio.1994.1105
Barateiro, A., Brites, D., & Fernandes, A. (2016). Oligodendrocyte
development and myelination in neurodevelopment: Molecular
mechanisms in health and disease. Curr Pharm Des,22(6),
656–679. https://doi.org/10.2174/1381612822666151204000636
Barateiro, A., & Fernandes, A. (2014). Temporal oligodendrocyte
lineage progression: In vitro models of proliferation, differentiation
and myelination. Biochim Biophys Acta,1843(9), 1917–1929.
https://doi.org/10.1016/j.bbamcr.2014.04.018
Baumann, N., & Pham-Dinh, D. (2001). Biology of oligodendrocyte
and myelin in the mammalian central nervous system. Physiol
Rev,81(2), 871–927. https://doi.org/10.1152/physrev.2001.81.2.
871
Bechler, M. E., Byrne, L., & Ffrench-Constant, C. (2015). CNS
Myelin sheath lengths are an intrinsic property of oligodendro-
cytes. Curr Biol,25(18), 2411–2416. https://doi.org/10.1016/j.
cub.2015.07.056
Bercury, K. K., Dai, J., Sachs, H. H., Ahrendsen, J. T., Wood, T. L.,
& Macklin, W. B. (2014). Conditional ablation of raptor or rictor
has differential impact on oligodendrocyte differentiation and
CNS myelination. J Neurosci,34(13), 4466–4480. https://doi.
org/10.1523/jneurosci.4314-13.2014
Blakemore, W. F. (1974). Pattern of remyelination in the CNS.
Nature,249(457), 577–578. https://doi.org/10.1038/249577a0
Brösamle, C., & Halpern, M. E. (2002). Characterization of myelina-
tion in the developing zebrafish. Glia,39(1), 47–57. https://doi.
org/10.1002/glia.10088
Brown, T. L., & Macklin, W. B. (2019). The actin cytoskeleton in
myelinating cells. Neurochem Res,45(3), 684–693. https://doi.
org/10.1007/s11064-019-02753-0
Bunge, M. B., Bunge, R. P., & Ris, H. (1961). Ultrastructural study
of remyelination in an experimental lesion in adult cat spinal
cord. J Biophys Biochem Cytol,10(1), 67–94. https://doi.org/
10.1083/jcb.10.1.67
Butt, A. M. (2006). Neurotransmitter-mediated calcium signalling
in oligodendrocyte physiology and pathology. Glia,54(7),
666–675. https://doi.org/10.1002/glia.20424
Calza, L., Fernandez, M., Giuliani, A., Aloe, L., & Giardino, L.
(2002). Thyroid hormone activates oligodendrocyte precursors
and increases a myelin-forming protein and NGF content in the
spinal cord during experimental allergic encephalomyelitis.
Proc Natl Acad Sci U S A,99(5), 3258–3263. https://doi.org/
10.1073/pnas.052704499
Cellerino, A., Carroll, P., Thoenen, H., & Barde, Y. A. (1997).
Reduced size of retinal ganglion cell axons and hypomyelination
Yu et al. 9

in mice lacking brain-derived neurotrophic factor. Mol Cell
Neurosci,9(5–6), 397–408. https://doi.org/10.1006/mcne.1997.
0641
Chang-Ileto, B., Frere, S. G., Chan, R. B., Voronov, S. V., Roux, A.,
& Di Paolo, G. (2011). Synaptojanin 1-mediated PI(4,5)P2
hydrolysis is modulated by membrane curvature and facilitates
membrane fission. Dev Cell,20(2), 206–218. https://doi.org/10.
1016/j.devcel.2010.12.008
Charles, P., Hernandez, M. P., Stankoff, B., Aigrot, M. S., Colin, C.,
Rougon, G., Zalc, B., & Lubetzki, C. (2000). Negative regulation
of central nervous system myelination by polysialylated-neural
cell adhesion molecule. Proc Natl Acad Sci U S A,97(13),
7585–7590. https://doi.org/10.1073/pnas.100076197
Chew, L. J., King, W. C., Kennedy, A., & Gallo, V. (2005).
Interferon-gamma inhibits cell cycle exit in differentiating oligo-
dendrocyte progenitor cells. Glia,52(2), 127–143. https://doi.org/
10.1002/glia.20232
Coman, I., Aigrot, M. S., Seilhean, D., Reynolds, R., Girault, J. A.,
Zalc, B., & Lubetzki, C. (2006). Nodal, paranodal and juxtapar-
anodal axonal proteins during demyelination and remyelination
in multiple sclerosis. Brain,129(12), 3186–3195. https://doi.
org/10.1093/brain/awl144
Dai, Z. M., Sun, S., Wang, C., Huang, H., Hu, X., Zhang, Z., Lu, Q. R.,
& Qiu, M. (2014). Stage-specific regulation of oligodendrocyte devel-
opment by Wnt/β-catenin signaling. J Neurosci,34(25), 8467–8473.
https://doi.org/10.1523/jneurosci.0311-14.2014
Dawson, M. R., Polito, A., Levine, J. M., & Reynolds, R. (2003).
NG2-expressing Glial progenitor cells: An abundant and wide-
spread population of cycling cells in the adult rat CNS. Mol
Cell Neurosci,24(2), 476–488. https://doi.org/10.1016/s1044-
7431(03)00210-0
Dietrich, R. B., Bradley, W. G., Zaragoza, E. J. t., Otto, R. J., Taira,
R. K., Wilson, G. H., & Kangarloo, H. (1988). MR evaluation of
early myelination patterns in normal and developmentally
delayed infants. AJR Am J Roentgenol,150(4), 889–896.
https://doi.org/10.2214/ajr.150.4.889
Dudek, H., Datta, S. R., Franke, T. F., Birnbaum, M. J., Yao, R.,
Cooper, G. M., Segal, R. A., Kaplan, D. R., & Greenberg, M. E.
(1997). Regulation of neuronal survival by the serine-threonine
protein kinase Akt. Science (New York, N.Y.),275(5300), 661–
665. https://doi.org/10.1126/science.275.5300.661
Edgar, J. M., & Garbern, J. (2004). The myelinated axon is depen-
dent on the myelinating cell for support and maintenance:
Molecules involved. J Neurosci Res,76(5), 593–598. https://
doi.org/10.1002/jnr.20063
Emery, B., & Lu, Q. R. (2015). Transcriptional and epigenetic regu-
lation of oligodendrocyte development and myelination in the
central nervous system. Cold Spring Harb Perspect Biol,7(9),
a020461. https://doi.org/10.1101/cshperspect.a020461
Fancy, S. P., Baranzini, S. E., Zhao, C., Yuk, D. I., Irvine, K. A.,
Kaing, S., Sanai, N., Franklin, R. J., & Rowitch, D. H. (2009).
Dysregulation of the wnt pathway inhibits timely myelination
and remyelination in the mammalian CNS. Genes Dev,23(13),
1571–1585. https://doi.org/10.1101/gad.1806309
Fancy, S. P., Harrington, E. P., Yuen, T. J., Silbereis, J. C., Zhao, C.,
Baranzini, S. E., Bruce, C. C., Otero, J. J., Huang, E. J., Nusse,
R., Franklin, R. J., & Rowitch, D. H. (2011). Axin2 as regulatory
and therapeutic target in newborn brain injury and remyelination.
Nat Neurosci,14(8), 1009–1016. https://doi.org/10.1038/nn.
2855
Fancy, S. P., Zhao, C., & Franklin, R. J. (2004). Increased expression
of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progen-
itor cells responding to demyelination in the adult CNS. Mol Cell
Neurosci,27(3), 247–254. https://doi.org/10.1016/j.mcn.2004.
06.015
Farías-Serratos, B. M., Lazcano, I., Villalobos, P., Darras, V. M., &
Orozco, A. (2021). Thyroid hormone deficiency during zebrafish
development impairs central nervous system myelination. PLoS
One,16(8), e0256207. https://doi.org/10.1371/journal.pone.
0256207
Feigenson, K., Reid, M., See, J., Crenshaw, E. B.III, & Grinspan, J.
B. (2009). Wnt signaling is sufficient to perturb oligodendrocyte
maturation. Mol Cell Neurosci,42(3), 255–265. https://doi.org/
10.1016/j.mcn.2009.07.010
Flores, A. I., Narayanan, S. P., Morse, E. N., Shick, H. E., Yin, X.,
Kidd, G., Avila, R. L., Kirschner, D. A., & Macklin, W. B.
(2008). Constitutively active akt induces enhanced myelination
in the CNS. J Neurosci,28(28), 7174–7183. https://doi.org/10.
1523/jneurosci.0150-08.2008
Foerster, S., Guzman de la Fuente, A., Kagawa, Y., Bartels, T.,
Owada, Y., & Franklin, R. J. M. (2020). The fatty acid binding
protein FABP7 is required for optimal oligodendrocyte differen-
tiation during myelination but not during remyelination. Glia,
68(7), 1410–1420. https://doi.org/10.1002/glia.23789
Franke, T. F., Kaplan, D. R., & Cantley, L. C. (1997). PI3K:
Downstream AKTion blocks apoptosis. Cell,88(4), 435–437.
https://doi.org/10.1016/s0092-8674(00)81883-8
Furusho, M., Ishii, A., & Bansal, R. (2017). Signaling by FGF recep-
tor 2, not FGF receptor 1, regulates myelin thickness through acti-
vation of ERK1/2-MAPK, which promotes mTORC1 activity in
an Akt-independent manner. J Neurosci,37(11), 2931–2946.
https://doi.org/10.1523/jneurosci.3316-16.2017
Gargareta, V. I., Reuschenbach, J., Siems, S. B., Sun, T., Piepkorn, L.,
Mangana, C., Späte, E., Goebbels, S., Huitinga, I., Möbius, W.,
Nave, K. A., Jahn, O., & Werner, H. B. (2022). Conservation
and divergence of myelin proteome and oligodendrocyte transcrip-
tome profiles between humans and mice. Elife,11, e77019. https://
doi.org/10.7554/eLife.77019.
Genoud, S., Lappe-Siefke, C., Goebbels, S., Radtke, F., Aguet, M.,
Scherer, S. S., Suter, U., Nave, K. A., & Mantei, N. (2002).
Notch1 control of oligodendrocyte differentiation in the spinal
cord. J Cell Biol,158(4), 709–718. https://doi.org/10.1083/jcb.
200202002
Gitik, M., Liraz-Zaltsman, S., Oldenborg, P. A., Reichert, F., &
Rotshenker, S. (2011). Myelin down-regulates myelin phagocy-
tosis by microglia and macrophages through interactions
between CD47 on myelin and SIRPα(signal regulatory
protein-α) on phagocytes. J Neuroinflammation,8, 24. https://
doi.org/10.1186/1742-2094-8-24
Goebbels, S., Oltrogge, J. H., Kemper, R., Heilmann, I., Bormuth, I.,
Wolfer, S., Wichert, S. P., Mobius, W., Liu, X., Lappe-Siefke, C.,
Rossner, M. J., Groszer, M., Suter, U., Frahm, J., Boretius, S., &
Nave, K. A. (2010). Elevated phosphatidylinositol 3,4,5-trisphosphate
in glia triggers cell-autonomous membrane wrapping and myeli-
nation. J Neurosci,30(26), 8953–8964. https://doi.org/10.1523/
jneurosci.0219-10.2010
Goebbels, S., Wieser, G. L., Pieper, A., Spitzer, S., Weege, B., Yan,
K., Edgar, J. M., Yagensky, O., Wichert, S. P., Agarwal, A.,
Karram, K., Renier, N., Tessier-Lavigne, M., Rossner, M. J.,
Káradóttir, R. T., & Nave, K. A. (2017). A neuronal PI(3,4,5)
10 ASN Neuro

P(3)-dependent program of oligodendrocyte precursor recruit-
ment and myelination. Nat Neurosci,20(1), 10–15. https://doi.
org/10.1038/nn.4425
Grinspan, J. B. (2015). Bone morphogenetic proteins: Inhibitors
of myelination in development and disease. Vitam Horm,99,
195–222. https://doi.org/10.1016/bs.vh.2015.05.005
Grinspan, J. B., Edell, E., Carpio, D. F., Beesley, J. S., Lavy, L.,
Pleasure, D., & Golden, J. A. (2000). Stage-specific effects of
bone morphogenetic proteins on the oligodendrocyte lineage. J
Neurobiol,43(1), 1–17. https://doi.org/10.1002/(SICI)1097-
4695(200004)43:1<1::AID-NEU1gt;3.0.CO;2-0
Hammond, E., Lang, J., Maeda, Y., Pleasure, D., Angus-Hill, M.,
Xu, J., Horiuchi, M., Deng, W., & Guo, F. (2015). The wnt effec-
tor transcription factor 7-like 2 positively regulates oligodendro-
cyte differentiation in a manner independent of wnt/β-catenin
signaling. J Neurosci,35(12), 5007–5022. https://doi.org/10.
1523/jneurosci.4787-14.2015
Harrington, E. P., Zhao, C., Fancy, S. P., Kaing, S., Franklin, R. J., &
Rowitch, D. H. (2010). Oligodendrocyte PTEN is required for
myelin and axonal integrity, not remyelination. Ann Neurol,
68(5), 703–716. https://doi.org/10.1002/ana.22090
Hildebrand, C., Remahl, S., Persson, H., & Bjartmar, C. (1993).
Myelinated nerve fibres in the CNS. Prog Neurobiol,40(3),
319–384. https://doi.org/10.1016/0301-0082(93)90015-k
Hines, J. H., Ravanelli, A. M., Schwindt, R., Scott, E. K., & Appel,
B. (2015). Neuronal activity biases axon selection for myelination
in vivo. Nat Neurosci,18(5), 683–689. https://doi.org/10.1038/
nn.3992
Hornig, J., Fröb, F., Vogl, M. R., Hermans-Borgmeyer, I., Tamm,
E. R., & Wegner, M. (2013). The transcription factors Sox0
and Myrf define an essential regulatory network module in differ-
entiating oligodendrocytes. PLoS Genet,9(10), e1003907.
https://doi.org/10.1371/journal.pgen.1003907
Hüppi, P. S., Warfield, S., Kikinis, R., Barnes, P. D., Zientara, G. P.,
Jolesz, F. A., Tsuji, M. K., & Volpe, J. J. (1998). Quantitative
magnetic resonance imaging of brain development in premature
and mature newborns. Ann Neurol,43(2), 224–235. https://doi.
org/10.1002/ana.410430213
Ishii, A., Furusho, M., Dupree, J. L., & Bansal, R. (2016). Strength
of ERK1/2 MAPK activation determines its effect on myelin
and axonal integrity in the adult CNS. J Neurosci,36(24),
6471–6487. https://doi.org/10.1523/jneurosci.0299-16.2016
Ishii, A., Furusho, M., Macklin, W., & Bansal, R. (2019).
Independent and cooperative roles of the Mek/ERK1/2-MAPK
and PI3 K/Akt/mTOR pathways during developmental myelina-
tion and in adulthood. Glia,67(7), 1277–1295. https://doi.org/10.
1002/glia.23602
Jahn, O., Siems, S. B., Kusch, K., Hesse, D., Jung, R. B., Liepold, T.,
Uecker, M., Sun, T., & Werner, H. B. (2020). The CNS myelin
proteome: Deep profile and persistence after post-mortem
delay. Front Cell Neurosci,14, 239. https://doi.org/10.3389/
fncel.2020.00239
Jakovcevski, I., Mo, Z., & Zecevic, N. (2007). Down-regulation of
the axonal polysialic acid-neural cell adhesion molecule expres-
sion coincides with the onset of myelination in the human fetal
forebrain. Neuroscience,149(2), 328–337. https://doi.org/10.
1016/j.neuroscience.2007.07.044
Jeffries, M. A., Urbanek, K., Torres, L., Wendell, S. G., Rubio, M. E.,
& Fyffe-Maricich, S. L. (2016). ERK1/2 Activation in preexisting
oligodendrocytes of adult mice drives new myelin synthesis and
enhanced CNS function. J Neurosci,36(35), 9186–9200. https://
doi.org/10.1523/jneurosci.1444-16.2016
Káradóttir, R., & Attwell, D. (2007). Neurotransmitter receptors in
the life and death of oligodendrocytes. Neuroscience,145(4),
1426–1438. https://doi.org/10.1016/j.neuroscience.2006.08.070
Kessaris, N., Fogarty, M., Iannarelli, P., Grist, M., Wegner, M., &
Richardson, W. D. (2006). Competing waves of oligodendrocytes
in the forebrain and postnatal elimination of an embryonic lineage.
Nat Neurosci,9(2), 173–179. https://doi.org/10.1038/nn1620
Kinney, H. C., Brody, B. A., Kloman, A. S., & Gilles, F. H. (1988).
Sequence of central nervous system myelination in human
infancy. II. Patterns of myelination in autopsied infants. J
Neuropathol Exp Neurol,47(3), 217–234. https://doi.org/10.
1097/00005072-198805000-00003
Kirby, B. B., Takada, N., Latimer, A. J., Shin, J., Carney, T. J.,
Kelsh, R. N., & Appel, B. (2006). In vivo time-lapse imaging
shows dynamic oligodendrocyte progenitor behavior during
zebrafish development. Nat Neurosci,9(12), 1506–1511.
https://doi.org/10.1038/nn1803
Kolodny, E. H. (1993). Dysmyelinating and demyelinating condi-
tions in infancy. Curr Opin Neurol Neurosurg,6(3), 379–386.
Lang, J., Maeda, Y., Bannerman, P., Xu, J., Horiuchi, M., Pleasure,
D., & Guo, F. (2013). Adenomatous polyposis coli regulates oli-
godendroglial development. J Neurosci,33(7), 3113–3130.
https://doi.org/10.1523/jneurosci.3467-12.2013
Lee, S., Chong, S. Y., Tuck, S. J., Corey, J. M., & Chan, J. R. (2013).
A rapid and reproducible assay for modeling myelination by oli-
godendrocytes using engineered nanofibers. Nat Protoc,8(4),
771–782. https://doi.org/10.1038/nprot.2013.039
Li, H., Lu, Y., Smith, H. K., & Richardson, W. D. (2007). Olig1 and
Sox10 interact synergistically to drive myelin basic protein tran-
scription in oligodendrocytes. J Neurosci,27(52), 14375–14382.
https://doi.org/10.1523/jneurosci.4456-07.2007
Ligon, K. L., Kesari, S., Kitada, M., Sun, T., Arnett, H. A., Alberta,
J. A., Anderson, D. J., Stiles, C. D., & Rowitch, D. H. (2006).
Development of NG2 neural progenitor cells requires Olig gene
function. Proc Natl Acad Sci U S A,103(20), 7853–7858.
https://doi.org/10.1073/pnas.0511001103
Liu, J., Dietz, K., DeLoyht, J. M., Pedre, X., Kelkar, D., Kaur, J.,
Vialou, V., Lobo, M. K., Dietz, D. M., Nestler, E. J., Dupree,
J., & Casaccia, P. (2012). Impaired adult myelination in the pre-
frontal cortex of socially isolated mice. Nat Neurosci,15(12),
1621–1623. https://doi.org/10.1038/nn.3263
Lu, Q. R., Sun, T., Zhu, Z., Ma, N., Garcia, M., Stiles, C. D., &
Rowitch, D. H. (2002). Common developmental requirement
for Olig function indicates a motor neuron/oligodendrocyte con-
nection. Cell,109(1), 75–86. https://doi.org/10.1016/s0092-
8674(02)00678-5
Lundgaard, I., Luzhynskaya, A., Stockley, J. H., Wang, Z., Evans,
K. A., Swire, M., Volbracht, K., Gautier, H. O., Franklin, R. J.,
Attwell, D., & Káradóttir, R. T. (2013). Neuregulin and BDNF
induce a switch to NMDA receptor-dependent myelination by oli-
godendrocytes. PLoS Biol,11(12), e1001743. https://doi.org/10.
1371/journal.pbio.1001743
Maire, C. L., Wegener, A., Kerninon, C., & Nait Oumesmar, B.
(2010). Gain-of-function of olig transcription factors enhances oli-
godendrogenesis and myelination. Stem Cells,28(9), 1611–1622.
https://doi.org/10.1002/stem.480
Makinodan, M., Rosen, K. M., Ito, S., & Corfas, G. (2012). A critical
period for social experience-dependent oligodendrocyte
Yu et al. 11

maturation and myelination. Science,337(6100), 1357–1360.
https://doi.org/10.1126/science.1220845
Mayoral, S. R., Etxeberria, A., Shen, Y. A., & Chan, J. R. (2018).
Initiation of CNS myelination in the optic nerve is dependent
on axon caliber. Cell Rep,25(3), 544–550.e543. https://doi.org/
10.1016/j.celrep.2018.09.052
McKinnon, R. D., Matsui, T., Dubois-Dalcq, M., & Aaronsont, S. A.
(1990). FGF modulates the PDGF-driven pathway of oligoden-
drocyte development. Neuron,5(5), 603–614. https://doi.org/
10.1016/0896-6273(90)90215-2
McMahon, H. T., & Boucrot, E. (2015). Membrane curvature at a
glance. J Cell Sci,128(6), 1065–1070. https://doi.org/10.1242/
jcs.114454
Mensch, S., Baraban, M., Almeida, R., Czopka, T., Ausborn, J., El
Manira, A., & Lyons, D. A. (2015). Synaptic vesicle release reg-
ulates myelin sheath number of individual oligodendrocytes in
vivo. Nat Neurosci,18(5), 628–630. https://doi.org/10.1038/nn.
3991
Mi, S., Hu, B., Hahm, K., Luo, Y., Kam Hui, E. S., Yuan, Q., Wong,
W. M., Wang, L., Su, H., Chu, T. H., Guo, J., Zhang, W., So, K. F.,
Pepinsky, B., Shao, Z., Graff, C., Garber, E., Jung, V., Wu, E. X., &
Wu, W. (2007). LINGO-1 antagonist promotes spinal cord remye-
lination and axonal integrity in MOG-induced experimental autoim-
mune encephalomyelitis. Nat Med,13(10), 1228–1233. https://doi.
org/10.1038/nm1664
Mi, S., Miller, R. H., Lee, X., Scott, M. L., Shulag-Morskaya, S.,
Shao, Z., Chang, J., Thill, G., Levesque, M., Zhang, M.,
Hession, C., Sah, D., Trapp, B., He, Z., Jung, V., McCoy,
J. M., & Pepinsky, R. B. (2005). LINGO-1 negatively regulates
myelination by oligodendrocytes. Nat Neurosci,8(6), 745–751.
https://doi.org/10.1038/nn1460
Miranda, M., Morici, J. F., Zanoni, M. B., & Bekinschtein, P. (2019).
Brain-derived neurotrophic factor: a key molecule for memory in
the healthy and the pathological brain. Front Cell Neurosci,13.
https://doi.org/10.3389/fncel.2019.00363
Mitew, S., Gobius, I., Fenlon, L. R., McDougall, S. J., Hawkes, D.,
Xing, Y. L., Bujalka, H., Gundlach, A. L., Richards, L. J.,
Kilpatrick, T. J., Merson, T. D., & Emery, B. (2018).
Pharmacogenetic stimulation of neuronal activity increases mye-
lination in an axon-specific manner. Nat Commun,9(1), 306.
https://doi.org/10.1038/s41467-017-02719-2
Monje, M. (2018). Myelin plasticity and nervous system function.
Ann Rev Neurosci,41,61–76. https://doi.org/10.1146/annurev-
neuro-080317-061853
Morreale de Escobar, G., Obregon, M. J., & Escobar del Rey, F.
(1987). Fetal and maternal thyroid hormones. Horm Res,26(1–4),
12–27. https://doi.org/10.1159/000180681
Morris, J. K., Willard, B. B., Yin, X., Jeserich, G., Kinter, M., &
Trapp, B. D. (2004). The 36 K protein of zebrafish CNS
myelin is a short-chain dehydrogenase. Glia,45(4), 378–391.
https://doi.org/10.1002/glia.10338
Münzel, E. J., Schaefer, K., Obirei, B., Kremmer, E., Burton, E. A.,
Kuscha, V., Becker, C. G., Brösamle, C., Williams, A., & Becker,
T. (2012). Claudin k is specifically expressed in cells that
form myelin during development of the nervous system and
regeneration of the optic nerve in adult zebrafish. Glia,60(2),
253–270. https://doi.org/10.1002/glia.21260
Narayanan, S. P., Flores, A. I., Wang, F., & Macklin, W. B. (2009).
Akt signals through the mammalian target of rapamycin pathway
to regulate CNS myelination. J Neurosci,29(21), 6860–6870.
https://doi.org/10.1523/jneurosci.0232-09.2009
Nave, K. A., & Werner, H. B. (2014). Myelination of the nervous
system: Mechanisms and functions. Ann Rev Cell Dev Biol,30,
503–533. https://doi.org/10.1146/annurev-cellbio-100913-
013101
Nawaz, S., Sanchez, P., Schmitt, S., Snaidero, N., Mitkovski, M.,
Velte, C., Bruckner, B. R., Alexopoulos, I., Czopka, T., Jung,
S. Y., Rhee, J. S., Janshoff, A., Witke, W., Schaap, I. A. T.,
Lyons, D. A., & Simons, M. (2015). Actin filament turnover
drives leading edge growth during myelin sheath formation in
the central nervous system. Dev Cell,34(2), 139–151. https://
doi.org/10.1016/j.devcel.2015.05.013
Newman, M. P., Féron, F., & Mackay-Sim, A. (2000). Growth factor
regulation of neurogenesis in adult olfactory epithelium.
Neuroscience,99(2), 343–350. https://doi.org/10.1016/s0306-
4522(00)00194-9
Nicholas, R. S., Stevens, S., Wing, M. G., & Compston, D. A.
(2002). Microglia-derived IGF-2 prevents TNFalpha induced
death of mature oligodendrocytes in vitro. J Neuroimmunol,
124(1–2), 36–44. https://doi.org/10.1016/s0165-5728(02)00011-
5
Noble, M., Murray, K., Stroobant, P., Waterfield, M. D., & Riddle, P.
(1988). Platelet-derived growth factor promotes division and motil-
ity and inhibits premature differentiation of the oligodendrocyte/
type-2 astrocyte progenitor cell. Nature,333(6173), 560–562.
https://doi.org/10.1038/333560a0
Paes de Faria, J., Kessaris, N., Andrew, P., Richardson, W. D., & Li,
H. (2014). New Olig1 null mice confirm a non-essential role for
Olig1 in oligodendrocyte development. BMC Neurosci,15, 12.
https://doi.org/10.1186/1471-2202-15-12
Pang, Y., Fan, L. W., Tien, L. T., Dai, X., Zheng, B., Cai, Z., Lin,
R. C., & Bhatt, A. (2013). Differential roles of astrocyte and
microglia in supporting oligodendrocyte development and myeli-
nation in vitro. Brain Behav,3(5), 503–514. https://doi.org/10.
1002/brb3.152
Park, H. C., Mehta, A., Richardson, J. S., & Appel, B. (2002). Olig2
is required for zebrafish primary motor neuron and oligodendro-
cyte development. Dev Biol,248(2), 356–368. https://doi.org/10.
1006/dbio.2002.0738
Pedraza, L., Huang, J. K., & Colman, D. (2009). Disposition of axonal
caspr with respect to glial cell membranes: Implications for the
process of myelination. J Neurosci Res,87(15), 3480–3491.
https://doi.org/10.1002/jnr.22004
Phan, B. N., Bohlen, J. F., Davis, B. A., Ye, Z., Chen, H. Y.,
Mayfield, B., Sripathy, S. R., Cerceo Page, S., Campbell,
M. N., Smith, H. L., Gallop, D., Kim, H., Thaxton, C. L.,
Simon, J. M., Burke, E. E., Shin, J. H., Kennedy, A. J., Sweatt,
J. D., Philpot, B. D., Jaffe, A. E., & Maher, B. J. (2020). A
myelin-related transcriptomic profile is shared by Pitt-Hopkins
syndrome models and human autism spectrum disorder. Nat
Neurosci,23(3), 375–385. https://doi.org/10.1038/s41593-019-
0578-x
Philips, T., & Rothstein, J. D. (2017). Oligodendroglia: Metabolic
supporters of neurons. J Clin Invest,127(9), 3271–3280.
https://doi.org/10.1172/JCI90610
Raff, M. C., Lillien, L. E., Richardson, W. D., Burne, J. F., & Noble,
M. D. (1988). Platelet-derived growth factor from astrocytes
drives the clock that times oligodendrocyte development in
12 ASN Neuro

culture. Nature,333(6173), 562–565. https://doi.org/10.1038/
333562a0
Readhead, C., & Hood, L. (1990). The dysmyelinating mouse muta-
tions shiverer (Shi) and myelin deficient (shimld). Behav Genet,
20(2), 213–234. https://doi.org/10.1007/BF01067791
Rosenberg, S. S., Kelland, E. E., Tokar, E., De la Torre, A. R., &
Chan, J. R. (2008). The geometric and spatial constraints of the
microenvironment induce oligodendrocyte differentiation. Proc
Natl Acad Sci U S A,105(38), 14662–14667. https://doi.org/10.
1073/pnas.0805640105
Schaefer, K., & Brösamle, C. (2009). Zwilling-A and -B, two related
myelin proteins of teleosts, which originate from a single bicis-
tronic transcript. Mol Biol Evol,26(3), 495–499. https://doi.org/
10.1093/molbev/msn298
Shen, S., Sandoval, J., Swiss, V. A., Li, J., Dupree, J., Franklin, R. J.,
& Casaccia-Bonnefil, P. (2008). Age-dependent epigenetic
control of differentiation inhibitors is critical for remyelination
efficiency. Nat Neurosci,11(9), 1024–1034. https://doi.org/10.
1038/nn.2172
Sherman, D. L., & Brophy, P. J. (2005). Mechanisms of axon ensheath-
ment and myelin growth. Nat Rev Neurosci,6(9), 683–690. https://
doi.org/10.1038/nrn1743
Shigemoto-Mogami, Y., Hoshikawa, K., Goldman, J. E., Sekino, Y.,
& Sato, K. (2014). Microglia enhance neurogenesis and oligo-
dendrogenesis in the early postnatal subventricular zone. J
Neurosci,34(6), 2231–2243. https://doi.org/10.1523/jneurosci.
1619-13.2014
Siems, S. B., Jahn, O., Hoodless, L. J., Jung, R. B., Hesse, D., Möbius,
W., Czopka, T., & Werner, H. B. (2021). Proteome profile of
myelin in the zebrafish brain. Front Cell Dev Biol,9, 640169.
https://doi.org/10.3389/fcell.2021.640169
Simons, M., & Nave, K. A. (2015). Oligodendrocytes: Myelination
and axonal support. Cold Spring Harbor Perspect Biol,8(1),
a020479. https://doi.org/10.1101/cshperspect.a020479
Snaidero, N., Mobius, W., Czopka, T., Hekking, L. H., Mathisen, C.,
Verkleij, D., Goebbels, S., Edgar, J., Merkler, D., Lyons, D. A.,
Nave, K. A., & Simons, M. (2014). Myelin membrane wrapping
of CNS axons by PI(3,4,5)P3-dependent polarized growth at the
inner tongue. Cell,156(1–2), 277–290. https://doi.org/10.1016/j.
cell.2013.11.044
Snaidero, N., & Simons, M. (2014). Myelination at a glance. J
Cell Sci,127(Pt 14), 2999–3004. https://doi.org/10.1242/jcs.
151043
Stankoff, B., Aigrot, M. S., Noël, F., Wattilliaux, A., Zalc, B., &
Lubetzki, C. (2002). Ciliary neurotrophic factor (CNTF)
enhances myelin formation: A novel role for CNTF and
CNTF-related molecules. J Neurosci,22(21), 9221–9227.
https://doi.org/10.1523/jneurosci.22-21-09221.2002
Stolt, C. C., Lommes, P., Friedrich, R. P., & Wegner, M. (2004).
Transcription factors Sox8 and Sox10 perform non-equivalent
roles during oligodendrocyte development despite functional
redundancy. Development,131(10), 2349–2358. https://doi.org/
10.1242/dev.01114
Stolt, C. C., Lommes, P., Sock, E., Chaboissier, M. C., Schedl, A., &
Wegner, M. (2003). The Sox9 transcription factor determines
glial fate choice in the developing spinal cord. Genes Dev,
17(13), 1677–1689. https://doi.org/10.1101/gad.259003
Stolt, C. C., Rehberg, S., Ader, M., Lommes, P., Riethmacher, D.,
Schachner, M., Bartsch, U., & Wegner, M. (2002). Terminal dif-
ferentiation of myelin-forming oligodendrocytes depends on the
transcription factor Sox10. Genes Dev,16(2), 165–170. https://
doi.org/10.1101/gad.215802
Sun, L. O., Mulinyawe, S. B., Collins, H. Y., Ibrahim, A., Li, Q.,
Simon, D. J., Tessier-Lavigne, M., & Barres, B. A. (2018).
Spatiotemporal control of CNS myelination by oligodendrocyte
programmed cell death through the TFEB-PUMA axis. Cell,
175(7), 1811–1826.e1821. https://doi.org/10.1016/j.cell.2018.
10.044
Takada, N., Kucenas, S., & Appel, B. (2010). Sox10 is necessary for
oligodendrocyte survival following axon wrapping. Glia,58(8),
996–1006. https://doi.org/10.1002/glia.20981
Taveggia, C., Zanazzi, G., Petrylak, A., Yano, H., Rosenbluth, J.,
Einheber, S., Xu, X., Esper, R. M., Loeb, J. A., Shrager, P.,
Chao, M. V., Falls, D. L., Role, L., & Salzer, J. L. (2005).
Neuregulin-1 type III determines the ensheathment fate of
axons. Neuron,47(5), 681–694. https://doi.org/10.1016/j.
neuron.2005.08.017
Tawk, M., Makoukji, J., Belle, M., Fonte, C., Trousson, A.,
Hawkins, T., Li, H., Ghandour, S., Schumacher, M., &
Massaad, C. (2011). Wnt/beta-catenin signaling is an essential
and direct driver of myelin gene expression and myelinogenesis.
J Neurosci,31(10), 3729–3742. https://doi.org/10.1523/
jneurosci.4270-10.2011
Thomason, E. J., Escalante, M., Osterhout, D. J., & Fuss, B. (2020).
The oligodendrocyte growth cone and its actin cytoskeleton: A
fundamental element for progenitor cell migration and CNS mye-
lination. Glia,68(7), 1329–1346. https://doi.org/10.1002/glia.
23735
Tiane, A., Schepers, M., Rombaut, B., Hupperts, R., Prickaerts, J.,
Hellings, N., van den Hove, D., & Vanmierlo, T. (2019). From
OPC to oligodendrocyte: An epigenetic journey. Cells,8(10),
1236. https://doi.org/10.3390/cells8101236
Timsit, S., Martinez, S., Allinquant, B., Peyron, F., Puelles, L., &
Zalc, B. (1995). Oligodendrocytes originate in a restricted zone
of the embryonic ventral neural tube defined by DM-20 mRNA
expression. J Neurosci,15(2), 1012–1024. https://doi.org/10.
1523/jneurosci.15-02-01012.1995
Traiffort, E., Kassoussi, A., Zahaf, A., & Laouarem, Y. (2020).
Astrocytes and microglia as major players of myelin production
in normal and pathological conditions. Front Cell Neurosci,14,
79. https://doi.org/10.3389/fncel.2020.00079
Tsai, H. H., Frost, E., To, V., Robinson, S., Ffrench-Constant, C.,
Geertman, R., Ransohoff, R. M., & Miller, R. H. (2002). The che-
mokine receptor CXCR2 controls positioning of oligodendrocyte
precursors in developing spinal cord by arresting their migration.
Cell,110(3), 373–383. https://doi.org/10.1016/s0092-8674(02)
00838-3
Tsai, H. H., Niu, J., Munji, R., Davalos, D., Chang, J., Zhang, H.,
Tien, A. C., Kuo, C. J., Chan, J. R., Daneman, R., & Fancy,
S. P. (2016). Oligodendrocyte precursors migrate along vascu-
lature in the developing nervous system. Science,351(6271),
379–384. https://doi.org/10.1126/science.aad3839
Vela, J. M., Molina-Holgado, E., Arévalo-Martín, A., Almazán, G.,
& Guaza, C. (2002). Interleukin-1 regulates proliferation and dif-
ferentiation of oligodendrocyte progenitor cells. Mol Cell
Neurosci,20(3), 489–502. https://doi.org/10.1006/mcne.2002.
1127
Wahl, S. E., McLane, L. E., Bercury, K. K., Macklin, W. B., &
Wood, T. L. (2014). Mammalian target of rapamycin promotes
oligodendrocyte differentiation, initiation and extent of CNS
Yu et al. 13

myelination. J Neurosci,34(13), 4453–4465. https://doi.org/10.
1523/jneurosci.4311-13.2014
Wang, S., Sdrulla, A. D., diSibio, G., Bush, G., Nofziger, D., Hicks,
C., Weinmaster, G., & Barres, B. A. (1998). Notch receptor acti-
vation inhibits oligodendrocyte differentiation. Neuron,21(1),
63–75. https://doi.org/10.1016/s0896-6273(00)80515-2
Watanabe, M., Hadzic, T., & Nishiyama, A. (2004). Transient upre-
gulation of Nkx2.2 expression in oligodendrocyte lineage cells
during remyelination. Glia,46(3), 311–322. https://doi.org/10.
1002/glia.20006
Wegener, A., Deboux, C., Bachelin, C., Frah, M., Kerninon, C.,
Seilhean, D., Weider, M., Wegner, M., & Nait-Oumesmar, B.
(2015). Gain of Olig2 function in oligodendrocyte progenitors
promotes remyelination. Brain,138(Pt 1), 120–135. https://doi.
org/10.1093/brain/awu375
Wolswijk, G., & Noble, M. (1989). Identification of an adult-specific
glial progenitor cell. Development,105(2), 387–400. https://doi.
org/10.1242/dev.105.2.387
Xin, M., Yue, T., Ma, Z., Wu, F. F., Gow, A., & Lu, Q. R. (2005).
Myelinogenesis and axonal recognition by oligodendrocytes in
brain are uncoupled in Olig1-null mice. J Neurosci,25(6),
1354–1365. https://doi.org/10.1523/jneurosci.3034-04.2005
Ye, P., Li, L., Richards, R. G., DiAugustine, R. P., & D’Ercole, A. J.
(2002). Myelination is altered in insulin-like growth factor-I null
mutant mice. J Neurosci,22(14), 6041–6051. https://doi.org/10.
1523/jneurosci.22-14-06041.2002
Yin, W., & Hu, B. (2014). Knockdown of Lingo1b protein promotes
myelination and oligodendrocyte differentiation in zebrafish. Exp
Neurol,251,72–83. https://doi.org/10.1016/j.expneurol.2013.11.
012
Zhang, K., Chen, S., Yang, Q., Guo, S., Chen, Q., Liu, Z., Li, L., Jiang,
M., Li, H., Hu, J., Pan, X., Deng, W., Xiao, N., Wang, B., Wang,
Z. X., Zhang, L., & Mo, W. (2022). The oligodendrocyte transcrip-
tion factor 2 OLIG2 regulates transcriptional repression during
myelinogenesis in rodents. Nat Commun,13(1), 1423. https://doi.
org/10.1038/s41467-022-29068-z
Zhao, Y. Y., Shi, X. Y., Qiu, X., Lu, W., Yang, S., Li, C., Chen, L.,
Zhang, L., Cheng, G. H., & Tang, Y. (2012). Enriched environ-
ment increases the myelinated nerve fibers of aged rat corpus cal-
losum. Anat Rec (Hoboken),295(6), 999–1005. https://doi.org/
10.1002/ar.22446
Zhu, X., Zuo, H., Maher, B. J., Serwanski, D. R., LoTurco, J. J., Lu,
Q. R., & Nishiyama, A. (2012). Olig2-dependent developmental
fate switch of NG2 cells. Development,139(13), 2299–2307.
https://doi.org/10.1242/dev.078873
Zuchero, J. B., Fu, M. M., Sloan, S. A., Ibrahim, A., Olson, A.,
Zaremba, A., Dugas, J. C., Wienbar, S., Caprariello, A. V.,
Kantor, C., Leonoudakis, D., Lariosa-Willingham, K.,
Kronenberg, G., Gertz, K., Soderling, S. H., Miller, R. H., &
Barres, B. A. (2015). CNS Myelin wrapping is driven by actin dis-
assembly. Dev Cell,34(2), 152–167. https://doi.org/10.1016/j.
devcel.2015.06.011
14 ASN Neuro