Axonal regulation of myelination by neuregulin 1
Klaus-Armin Nave1,2 and James L Salzer3
Neuregulins comprise a family of epidermal growth factor-like
ligands that interact with ErbB receptor tyrosine kinases to
control many aspects of neural development. One of the most
dramatic effects of neuregulin-1 is on glial cell differentiation.
The membrane-bound neuregulin-1 type III isoform is an axonal
ligand for glial ErbB receptors that regulates the early Schwann
cell lineage, including the generation of precursors. Recent
studies have shown that the amount of neuregulin-1 type III
expressed on axons also dictates the glial phenotype, with a
threshold level triggering Schwann cell myelination.
Remarkably, neuregulin-1 type III also regulates Schwann cell
membrane growth to adjust myelin sheath thickness to match
axon caliber precisely. Whether this signaling system operates
in central nervous system myelination remains an open
question of major importance for human demyelinating
diseases.
Addresses
1
Max Planck Institute of Experimental Medicine, D-37075 Goettingen,
Germany
2
Hertie Institute of Multiple Sclerosis Research, Goettingen, Germany
3
Departments of Cell Biology and Neurology, and the Molecular
Neurobiology Program, Skirball Institute of Biomolecular Medicine, New
York University School of Medicine, New York, NY 10016, USA
Corresponding author: Nave, Klaus-Armin ([email protected])
Current Opinion in Neurobiology 2006, 16:492–500
This review comes from a themed issue on
Neuronal and glial cell biology
Edited by Kelsey C Martin and Elior Peles
Available online 7th September 2006
0959-4388/$ – see front matter
# 2006 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.conb.2006.08.008
Introduction
Reciprocal interactions between neurons and glia are
crucial for the organization and function of the nervous
system, from neurogenesis in embryonic development to
synaptic plasticity in the adult brain. Glial cells that
synthesize myelin are essential for normal motor and
cognitive functions, with the fine tuning of myelination
contributing to the millisecond precision of the nervous
system [1]. Furthermore, myelin-forming glial cells are
also required for the long-term integrity of axons, independently of myelin itself [2,3]. Axons, in turn, crucially
regulate the behavior of myelinating glia: that is, Schwann
cells and oligodendrocytes. However, the molecular
mechanisms by which neurons and glial cells communicate remain poorly understood.
Current Opinion in Neurobiology 2006, 16:492–500
In this review, we describe recent progress in elucidating
the mechanisms by which motor and sensory axons in the
peripheral nervous system (PNS) regulate the development and differentiation of Schwann cells, most strikingly
during myelination. Unexpectedly, a single growth factor,
neuregulin-1 (NRG1), has emerged as the pivotal signal
that controls Schwann cells at every stage of the lineage.
Neuregulin-1 and ErbB receptors
The Neuregulin-1 (NRG1) family comprises more than
15 membrane-associated and secreted proteins [4,5].
These are derived from one of the largest mammalian
genes (on human chromosome 8p22 and mouse chromosome 8A3) and are generated by use of multiple transcription sites and by extensive alternative RNA splicing
[6]. All NRG1 isoforms share an epidermal growth factor
(EGF)-like signaling domain that is necessary and sufficient for activation of their receptors. NRG1 isoforms are
subdivided into several subtypes on the basis of their
distinct amino-termini [4,7]. NRG1 type I (also known as
heregulin, neu differentiation factor, or acetylcholine
receptor-inducing activity [ARIA]) and NRG1 type II
(also known as glial growth factor [GGF]) have N-terminal immunoglobulin-like domains. Transmembrane
forms of NRG1 undergo proteolytic cleavage by metalloproteinases (MP), including TACE (tumor-necrosis
factor-a-converting enzyme) [8]. As a consequence,
NRG1 type I and II are shed from the neuronal cell
surface and function as paracrine signaling molecules
(schematically depicted in Figure 1). NRG1 type III is
defined by its cysteine-rich domain (CRD), which functions as a second transmembrane domain. Consequently,
NRG1 type III remains tethered to the cell surface after
cleavage and functions as a juxtacrine signal [9]. In
addition, exons encoding shorter amino termini of
NRG1 have been identified by sequence analysis
(referred to as types IV–VI), but these isofoms have
not been further characterized [10]. NRG1 expression
is not specific to the nervous system, it also has a major
role in cardiac and mammary tissue development
(reviewed in [11]). Indeed, mice lacking NRG1, or its
receptors (ErbB2, ErbB3 and ErbB4), are embryonic
lethal because NRG1–ErbB signaling is essential for
cardiac development.
Within the nervous system, NRG1 types I and III are the
most abundant forms and have been detected in many
projection neurons, most notably in spinal motor neurons
and dorsal root ganglia (DRG) neurons, but also in glia
[4,12]. In addition to the axon–glia signaling detailed
below, the proposed functions of NRG1 include the development of motor endplates, migration of interneurons, and
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Axonal regulation of myelination by neuregulin 1 Nave and Salzer 493
Figure 1
NRG1 isoforms: membrane disposition and signalling. (a) Types I and II are synthesized as single pass transmembrane proteins; Type III has
two transmembrane domains. (b) With metalloproteinase (MP) cleavage, types I and II are shed as paracrine signals, type III remains tethered
through its cysteine rich domain (CRD) and is a juxtacrine signal; this cleavage is enhanced by neurotrophins released by Schwann cells. The
cytoplasmic domain undergoes further cleavage stimulated by binding of ErbB receptors to NRG1, followed by translocation to the nucleus. See [4] for
additional details.
synaptogenesis and synaptic plasticity in the CNS [5].
Many NRG1-expressing neurons also express transcripts
for NRG2 and NRG3, two structurally related growth
factors with EGF-like signaling domains, the function of
which in the nervous system remains largely unknown
[12,13].
ErbB receptors
NRG1 isoforms mediate their effects by binding to ErbB
receptors, members of the EGF receptor superfamily [14].
NRG1 binds to either ErbB3, which lacks an active kinase
domain, or ErbB4, which has such a kinase domain; each
receptor, in turn, can heterodimerize with ErbB2, which
cannot bind NRG1 directly but also has an active kinase
domain. ErbB receptors dimerize not by virtue of a bridging effect of NRG1, but following a ligand-activated
conformational change in the ectodomain of ErbB3 or
ErbB4 [15]. Crystallographic data indicate that ErbB2
constitutively exposes a dimerization loop required to
form heterodimers with ligand-activated ErbB3 or ErbB4
receptors. Because the ability of ErbB2 to form homodimers is poor, and ErbB4 is minimally expressed by
Schwann cells, ErbB2–ErbB3 is the relevant NRG1
Schwann cell receptor. NRG1 binding induces ErbB2–
ErbB3 heterodimer formation, which leads to receptor
cross-phosphorylation, recruitment of SH3-containing
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adaptor molecules and activation of downstream signaling
pathways (see below). Whereas Schwann cells principally
express ErbB2 and ErbB3, cells in the oligodendrocyte
lineage express all three ErbB receptors, in a developmentally regulated manner, in addition to the EGFR (ErbB1),
indicating significant complexity of potential ErbB receptor heterodimers and downstream signaling events in these
cells [16,17].
NRG1 ‘back signaling’
Intriguingly, NRG1 might also signal bidirectionally. Binding of recombinantly produced ‘soluble’ ErbB receptors to
membrane-bound NRG1 type III of transfected neurons
results in proteolytic cleavage of NRG1, releasing its
cytoplasmic C-terminal domain (CTD) from the membrane [18]. Remarkably, the CTD then rapidly translocates
into the cell nucleus of the cultured neurons where it
activates transcription and enhances survival. Whether
NRG1 ‘backsignaling’ occurs in vivo, particularly when
NRG1 expressed on the axon is engaged by ErbB receptors
of myelinating glia, remains to be established. It will also be
important to determine whether loss of the anti-apoptotic
effect of the CTD is normally responsible for the degeneration of dorsal root ganglion (DRG) and motor neurons
that is observed in NRG1 null mutant mice. Alternatively,
conventional NRG1 (forward) signaling could elicit
Current Opinion in Neurobiology 2006, 16:492–500
494 Neuronal and glial cell biology
reciprocal trophic support of ensheathed axons, such as
through NRG1-stimulated release of neurotrophins by glia
[19]. Finally, the cytoplasmic tail of NRG1 has been
reported to interact directly with LIM kinase, a regulator
of the actin cytoskeleton [20]; the biological significance of
this interaction is not yet established.
indicate that final matching of SCPs to axons is mediated
through competition for a NRG1-mediated survival signal [24–26]. NRG1 type III is the key isoform required
for SCP survival and migration during early embryogenesis [26].
The role of NRG1 in Schwann cell myelination
Threshold levels of NRG1 type III are an instructive
signal for myelination
NRG1 has a crucial role at essentially every developmental stage of Schwann cells, as first indicated by both
culture studies and analysis of knockout mice [21,22].
These functions include promoting the gliogenic fate of
trunk neural crest cells, the migration of Schwann cell
precursors (SCP) along axons, and their subsequent
proliferation and survival induced by axons. A recent
study, analyzing zebrafish ErbB mutants, strongly supports the key role of NRG1–ErbB signaling in SCP
proliferation and directed migration along axons
although, surprisingly, not for survival [23]. This result
contrasts with studies in rodents and chick, which
Once generated, SCPs differentiate into mature Schwann
cells that either ensheath multiple small, unmyelinated
axons, forming a Remak bundle, or sort larger axons into a
1:1 relationship that they subsequently myelinate (schematically summarized in Figure 2). These alternative
phenotypes are distinguishable not only by their anatomic
relationship to the axon but by the repertoire of transcription factors and proteins that Schwann cells express. The
axon determines this binary choice in Schwann cell
phenotypes, as first demonstrated in classic studies performed over a century ago in which myelinated and nonmyelinated nerves were cross-anastomosed [27]. As
Figure 2
Axonal NRG1 regulates successive steps of Schwann cell differentiation. (a) Schwann cells (in blue) arise from neural crest precursor cells
(in green) and interact with both large and small caliber axons of spinal motor and sensory neurons. During embryogenesis, NRG1 on
the axon regulates Schwann cell development by activating ErbB signaling cascades, thereby promoting Schwann cell differentiation and
expansion. The amount of NRG1 type III on the axon detected by committed Schwann cells, which is a function of axon size and NRG1
levels, then drives them either into segregating single axons and myelination (top), or into a non-myelinating phenotype and formation of
a Remak bundle (bottom). Above threshold levels, NRG1 type III signals axon size to Schwann cells to optimize myelin sheath thickness.
(b) In mouse mutants lacking NRG1 (/), in heterozygous NRG1 (+/) mice, and in transgenic NRG1 overexpressing mice, the amount
of myelin made by Schwann cells varies directly as a function of axonal NRG1 type III levels (indicated by yellow dots) rather than as a function
of axon diameter. See [30,32] for further details.
Current Opinion in Neurobiology 2006, 16:492–500
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Axonal regulation of myelination by neuregulin 1 Nave and Salzer 495
myelination in the PNS typically commences around
axons with a diameter of 1 mm or greater, it was initially
posited that a critical axonal diameter was the trigger for
Schwann cell myelination [28,29].
Recent studies by Taveggia et al. [30] on the role of
NRG1 in myelination suggest that the level of NRG1
type III on the axon, rather than axon diameter per se, is
the key instructive signal for myelination. Expression of
NRG1 type III on the axon correlates with the
ensheathment fate of axons: unmyelinated, autonomic
neurons express low levels of NRG1 type III on the
axon surface, whereas brain-derived neurotrophic factor
(BDNF) and neurotrophin-3 (NT-3) dependent dorsal
root ganglion (DRG) neurons, the axons of which are
heavily myelinated, express high levels. DRG axons
from NRG1 type III null mice are not myelinated by
Schwann cells in cocultures and do not induce myelinspecific structural proteins or transcription factors, thus
demonstrating that axonal NRG1 type III is essential for
myelination [30]. Furthermore, mice haploinsufficient
for NRG1 type III have a significantly higher proportion
of axons that are persistently unmyelinated [30].
Accordingly, pharmacologic inhibitors of ErbB receptors
demonstrated a requirement for NRG1 signaling for the
initiation of myelination in zebrafish [23]. Strikingly,
forced expression of NRG1 type III in the post-ganglionic fibers of sympathetic neurons converts these
normally unmyelinated fibers to myelinated ones
in vitro [30]. Likewise, in transgenic mice, overexpression of NRG1 type III induces earlier onset of myelination in the PNS than normal, and results in myelination
of very small-caliber C-fiber axons that would normally
be unmyelinated (M Schwab and KA Nave, unpublished). Taken together, these results suggest that
threshold levels of NRG1 type III provide the long
sought instructive signal that triggers Schwann cell
myelination (Figure 2).
NRG1 type III levels regulate myelin thickness
NRG1–ErbB signaling has also been recruited for the
important regulatory step associated with the final stage
of Schwann cell differentiation: the quantitative control
of myelin sheath thickness. When aiming for the most
rapid impulse propagation, which is a function of axon
caliber and myelination, the optimal myelin thickness is
reached when the ‘g-ratio’ (i.e. the numeric ratio between
the diameter of the axon cylinder and that of the myelinated axon) is close to 0.68. For most vertebrates, this
ratio is remarkably well maintained for peripheral axons
and their myelinating glia independent of the specific
axon diameter as first noted by Donaldson and Hoke [31].
This requires axon size to be perceived by myelinating
Schwann cells, to make the correct number of myelin
wraps. Michailov et al. [32] demonstrated that this axon
size information is encoded, at least in part, by the amount
of membrane-associated NRG1 type III displayed on the
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axon surface. Altering this communication impacts on the
g-ratio of myelinated axons. Thus, heterozygous NRG1
type III null mutant mice, that display roughly 50% of the
NRG1, are hypomyelinated, have commensurate reduction in myelin transcription factors and exhibit reduced
nerve conduction velocities [30,32]. By contrast, transgenic mice that overexpress NRG1 in dorsal root ganglia
and motor neurons (under control of the neuronal ThyI
promoter) become hypermyelinated [32]. Axon-toSchwann cell signaling appears specific to NRG1 type
III, as transgenic mice that overexpress the secreted
NRG1 type I are not hypermyelinated; this specificity
might reflect a requirement for juxtacrine signaling characteristic of the type III isoform [9,30,32].
Whereas NRG1 has emerged as the rate-limiting factor of
myelin growth control, ErbB2 and ErbB3 are expressed at
saturating levels [32]. They must be dramatically reduced
to disrupt myelination, such as in a conditional mouse
mutant carrying the Schwann cell-specific null mutation
of the ErbB2 gene [33]. Similarly, mice that express a
dominant-negative ErbB receptor in Schwann cells under
control of the 20 ,30 -cyclic nucleotide phosphodiesterase
(CNPase) promoter are hypomyelinated and have thinner
myelin sheaths than normal [34]. The length of myelin
internodes in mice expressing a dominant negative ErbB
receptor is also shorter than normal [34], in contrast to
mice with reduced NRG1 dosages that have internodes of
normal length [32].
Taken together, these studies support a model in which
threshold levels of NRG1 type III are required to trigger
myelination. Above this threshold, the amount of myelin
formed is graded to the amount of NRG1 type III presented by the axon to the Schwann cell — an amount likely
to reflect both the concentration of NRG1 type III at the
membrane and the axon surface area (a function of axon
diameter). These results also provide a mechanism by
which axons, through differing levels of NRG1 type III,
coordinate Schwann cell numbers to their alternative phenotypes. Thus, axons that express higher levels of NRG1
type III generate the additional Schwann cells required to
establish the 1:1 relationship characteristic of myelinated
fibers and, subsequently, drive axon segregation and
myelination.
Role of NRG1 in myelin maintenance and the injury
response
Recent studies have addressed whether ongoing NRG1
signaling is required to maintain the axon-myelinating
Schwann cell unit after it has formed, and whether
NRG1 has a role during Wallerian degeneration. To
address the first question, Atanasoski et al. [35] ablated
the ErbB2 receptor gene in adult myelinating Schwann
cells using tamoxifen-inducible Cre recombinase,
expressed under the control of the proteolipid protein
promoter (PLP); they found, surprisingly, that myelin
Current Opinion in Neurobiology 2006, 16:492–500
496 Neuronal and glial cell biology
sheaths were unaffected even after two months. Results
from this study strongly suggest that ongoing ErbB2 signaling, and by inference NRG1 activity, is dispensable for
maintenance of the myelin sheath in the adult. This result
is also consistent with the maintenance of myelin sheaths
in neuron–Schwann cell cocultures even when continuously treated with pharmacologic inhibitors of signaling
pathways activated by NRG1 [36].
NRG1 has also been considered a candidate to mediate
the Schwann cell response to injury as it is persistently
expressed by adult axons [30,32,37], and could therefore be released during Wallerian degeneration to stimulate Schwann cell proliferation. In support, ErbB2 is
rapidly activated (phosphorylated) within minutes of
injury [38] followed by a delayed, and sustained (over
days), upregulation of ErbB receptors and NRG1 isoforms by Schwann cells [37,39]. In addition, several
investigators have reported that addition of NRG1 type
II results in demyelination and proliferation in cocultures [38,40,41] or when expressed as a transgene in
Schwann cells under the control of the P0 promoter
in vivo [42]. These findings suggest that NRG1 isoforms
could function as an injury signal, or contribute to nerve
pathology, when either misexpressed or aberrantly presented to the outer (abaxonal) Schwann cell membrane.
Important support for a role of NRG1–ErbB signaling in
the injury response was also provided by studies in
which pharmacologic inhibition of ErbB2 receptors
blocked Schwann cell proliferation after injury in vitro
and in vivo [38]. Surprisingly, in a second study in
which ErbB2 expression was conditionally ablated
in vivo before injury, no effect on Schwann cell proliferation during Wallerian degeneration was seen [35].
The reasons for the discrepancy between these two
studies is not yet clear.
NRG1 regulates axon–Schwann cell interactions in
Remak fibers
Although axonal NRG1 is the primary signal for immature
Schwann cells to adopt the myelin-forming phenotype
([30] and Schwab MH, Humml C, Nave K-A, unpublished), NRG1–ErbB signaling is also important for the
organization and function of adult non-myelinating
Schwann cells. Adult heterozygous NRG1 Type III null
mice exhibit impaired sorting of unmyelinated axons into
separate Schwann cell pockets, which instead frequently
persist as large bundles [30]. These results indicate a
more general role for NRG1 signals in axon sorting by
Schwann cells. Overexpression of a truncated (dominantnegative) ErbB4 receptor under control of the glial fibrillary acidic protein (GFAP) promoter in Remak Schwann
cells also leads to significant abnormalities. These include
progressive loss of small C-fiber axons, which leads to
death of DRG neurons, pain insensitivity and a novel
neuropathy phenotype; neuron cell loss might reflect
significant reductions of glial support, potentially because
Current Opinion in Neurobiology 2006, 16:492–500
of impaired glial-derived neurotrophic factor (GDNF)
expression by Schwann cells [43]. These observations
also reveal that ensheathing glial cells in the PNS, as
in the CNS [3], have a primary axon-protective function,
independent of myelination.
NRG1-activated signaling pathways and myelination
The signaling pathways by which axons, through NRG1,
promote Schwann cell myelination have also begun to
emerge. NRG1 robustly activates mitogen-activated protein (MAP) kinase and PtdIns 3-kinase pathways in cultured Schwann cells (reviewed in [5,44]). Axonal contact
also robustly activates these signaling pathways in
Schwann cells [36] — NRG1 type III is the key neuronal
signal that mediates PtdIns 3-kinase activation, whereas
other signals, distinct from NRG1 type III but not yet
identified, activate MAP kinase [30]. Activation of the
PtdIns 3-kinase pathway, and its downstream effectors,
notably the serine-threonine kinase Akt, are crucial for the
trophic, proliferative and differentiative responses of
Schwann cells to axons and NRG1. Pharmacologic inhibition of PtdIns 3-kinase blocks the ability of axons to
promote Schwann cell proliferation, survival and induction
of myelination [36]. Expression of dominant negative
forms of PtdIns 3-kinase or Akt in Schwann cells inhibits
myelination in vitro, whereas overexpression of PtdIns
3-kinase or activated Akt promote myelin protein expression in vitro and enhanced myelin sheath formation during
regeneration in vivo [45]. In contrast to its promyelinating
effects, activation of MAP kinase pathways inhibits myelination [45] and causes myelinating Schwann cells to
dedifferentiate and proliferate [41]. This has led to the
notion that the balance between these two major signaling
pathways determines the differentiative state of Schwann
cells [45].
Two important signals that also regulate Schwann cell
differentiation, laminin in the extracellular matrix
(ECM) and cAMP-dependent pathways, were recently
implicated in NRG1-dependent signaling. Mice deficient in laminin expression fail to ensheath axons appropriately and exhibit markedly reduced ErbB–PtdIns-3
kinase signaling associated with increased Schwann cell
apoptosis [46]. Impaired ErbB signaling might result
from aberrant physical interactions between Schwann
cells and axons and/or altered co-signaling by ECM
components. Laminin, through interaction with integrin
receptors, has been reported to switch the signaling
pathways mediated by soluble NRG1 isoforms in cultured oligodendrocytes [47] and so might also qualitiatively affect Schwann cell signaling activated by NRG1.
Moreover, addition of cAMP analogs to cultured
Schwann cells mimics the effect of axonal contact and
has synergistic effects with NRG1 [22]. Elevated
cAMP increases ErbB receptor expression and leads
to sustained activation of NRG1-dependent signaling
pathways [48,49].
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Axonal regulation of myelination by neuregulin 1 Nave and Salzer 497
A role for neurotrophins in axonal NRG1
signaling
Neurotrophins exert multiple effects on developing glia,
including Schwann cells and oligodendrocytes. A remarkable ability to stimulate Schwann cell differentiation
in vivo was observed by Griffin and co-workers [50],
who found that the injection of glial-derived growth factor
(GDNF) into rats caused non-myelinating Schwann cells
to proliferate and even to myelinate some of the very
small caliber C-fiber axons. These experiments do not
distinguish between a direct effect on glia and an indirect
one (e.g. by stimulating axons to express NRG1). Esper
and Loeb [51] demonstrated that nerve growth factor
(NGF) and GDNF, both of which are expressed by
Schwann cells, induce the rapid release of NRG1 from
the axons of cultured DRG neurons and motor neurons.
Although the molecular mechanisms are not fully understood, this neurotrophin-inducible NRG1 release occurs
within minutes, is dose-dependent, and can be mimicked
by protein kinase C activation. It probably involves
regulated proteolytic processing of cleavable NRG1 isoforms, such as transmembrane type I and II isoforms.
Taken together with evidence that NRG1 promotes
GDNF expression by Schwann cells in Remak fibers
[43], it appears that a regulatory loop of glial-axon-glial
signaling through growth factors determines both neuronal survival and Schwann cell differentiation in the peripheral nervous system.
Independently, Chan et al. [52] showed that neurotrophins have strong but opposing effects on myelination by
Schwann cells versus oligodendrocytes. In DRG–
Schwann cell cocultures, adding NGF to the medium
promoted myelination, whereas in DRG–oligodendrocyte cocultures, NGF had an inhibitory effect. The
requirement of (neuronal) TrkA receptors and the results
of experiments with Campenot chambers suggest that
neurons, not glial cells, are the crucial target cells of NGF
signaling. Although the idea that neurons are stimulated
by NGF is in agreement with the data of Esper and Loeb
[51], the divergent responses of Schwann cells and oligodendrocytes to DRG neurons treated with NGF is
unexpected. It contradicts the view that axons that project from the CNS into the PNS (and vice versa) are
uniformly myelinated because they provide the same
signals to oligodendrocytes and Schwann cells. Modifying
this view might help to elucidate temporal differences in
the onset of CNS and PNS myelination. It is not yet
known whether some of these effects involve NRG1
signaling. The relevance of these in vitro observations
in normal development remains to be determined, possibly by careful analysis of existing mouse mutants.
The role of NRG1 in oligodendrocyte
development
An obvious question is whether NRG1 type III also
regulates oligodendrocyte myelination — this important
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issue is yet to be resolved. However, several studies
suggest that NRG1–ErbB signaling might regulate oligodendrocyte development and provide insights into its
potential role during differentiation.
Initial studies in which oligodendrocyte progenitor cell
(OPC) cultures were supplemented with soluble NRG1
isoforms suggested that NRG1 has trophic and mitogenic
effects on cells in the oligodendrocyte lineage; their
effects on differentiation varied considerably between
studies (reviewed in [53]). Analysis of the role of
NRG1 in a more physiologic context has been confounded by the early embryonic lethality of NRG1 and
ErbB receptor knockouts. As an alterative strategy, the
role of NRG1 and ErbB receptors in oligodendrocyte
development has been analyzed during the ex vivo development of embryonic spinal cord from mice deficient in
these proteins. These studies suggest a complex role of
NRG–ErbB signaling in the oligodendrocyte lineage.
OPC development was reported to be markedly deficient
in spinal cord explants from NRG1 null mice [54]. Loss of
ErbB2 likewise impaired OPC differentiation [55]. However, loss of ErbB3 had no effect on oligodendrocyte
differentiation or myelination [56], whereas loss of ErbB4
paradoxically enhanced oligodendrocyte differentiation
[17]. It is probably the case that altered rather than
completely absent ErbB signaling in these receptor
knockouts accounts for these widely divergent effects
on oligodendrocyte differentiation. Mice that express a
chimeric, dominant negative ErbB receptor protein to
inhibit ErbB signaling broadly in the oligodendrocyte
lineage had increased numbers of progenitor cells,
reduced numbers of mature oligodendrocytes, and were
hypomyelinated [57]. This hypomyelination suggests
that ErbB signaling, and potentially NRG1 or related
ligands, could regulate CNS myelination. In the future,
analyses of conditional NRG1 and ErbB receptor knockouts are expected to more precisely delineate the important issue of the role of this signaling pathway in the
oligodendrocyte lineage.
Clinical implications
Null mutations of the NRG1 gene and its receptors are
embryonically lethal in mice [7], suggesting that human
NRG1 loss-of-functions are unlikely to be a primary cause
of disease. However, the many roles of NRG1 in glial cell
development suggest that dysregulated NRG1 expression (or abnormal Nrg1-ErbB-PI3K signaling) contributes
to disorders of myelin as a disease modifier or a genetic
risk factor. Although this is an interesting possibility, it
remains speculative as no evidence directly links NRG1
to myelin disorders as of yet.
One potential example is the inherited demyelinating
neuropathies (Charcot-Marie-Tooth [CMT] disease
type 1) of the peripheral nervous system that result
from the abnormal expression of myelin membrane
Current Opinion in Neurobiology 2006, 16:492–500
498 Neuronal and glial cell biology
proteins [58,59] including P0, PMP22, and connexin32.
Non-specific pathological features of CMT1 include dysmyelination and ‘onion bulb’ formation by supernumerary
Schwann cells. It is intriguing to speculate that perturbed
physical interactions, for example between axons and
ensheathing glial membranes, secondary to abnormal
expression of myelin proteins or gap junction proteins,
alter NRG1-ErbB-PI3K signaling, and contribute to the
CMT1 pathology.
In the adult central nervous system, multiple sclerosis
(MS) lesions often fail to remyelinate, despite the presence of oligodendrocytes and OPC [60]. If remyelination
occurs at all, the resulting sheaths are abnormally thin
[61]. This is reminiscent of the thin sheaths of remyelinated peripheral nerves [62] and the hypomyelination
seen in the PNS of mice with reduced NRG1 gene dosage
[30,32]. An intriguing possibility is that the steady-state
levels of NRG1 or related growth factors on myelinated
axons in the adult CNS (or PNS) are reduced below the
level required for robust remyelination, particularly in
demyelinated regions [63,64]. These ideas can be experimentally tested in mice with a genetically modified NRG1
expression level, when challenged by either an experimental autoimmune encephalomyelitis (EAE) or a toxininduced demyelination to undergo spontaneous remyelination. Earlier reports that the systemic application of
recombinant NRG1 improved the course of EAE in mice,
with respect to disease onset and severity [63,65], contrasts with the inability to improve the degree of remyelination in toxin-induced rat CNS lesions [66]. This
suggests that the beneficial effects of systemic NRG1
administration have been indirect, for example, through
immune modulation. It is our experience from experiments in the peripheral nervous system that functional
NRG1 signaling to myelinating glia must be presented
directly by the axon [30,32], whereas ectopic stimulation by soluble NRG1 might even have detrimental
effects on myelination [40]. This might reflect the
requirement for NRG1 to signal in a juxtacrine mode,
or that NRG1 only promotes oligodendrocyte differentiation in the context of laminin–integrin signaling at the
axon–glial interface [47].
Finally, there are intriguing links between NRG1 expression, myelination and neuropsychiatric disorders. Stefansson and coworkers [67] reported the association of single
nucleotide polymorphisms (SNPs) in the 50 region of the
NRG1 gene with schizophrenia in the Icelandic population, an association now confirmed in other populations
[68]. The molecular consequences of the crucial NRG1
‘at risk’ haplotype are still unclear as the SNPs all correspond to non-coding variants, but recent evidence suggests alterations of expression of NRG1 types I, III and IV
[6,69]. Because NRG1–ErbB signaling in the CNS affects
oligodendrocyte development in addition to neuroblast
migration and glutamatergic synapse function, NRG1 is a
Current Opinion in Neurobiology 2006, 16:492–500
plausible susceptibility gene to contribute to human
schizophrenia [70]. Interestingly, CNS myelin abnormalities have also been independently associated with
schizophrenia and other neuropsychiatric diseases on
the basis of gene array and imaging studies [71,72], adding
credence to a potential glial contribution.
Outlook and conclusions
The identification of NRG1 as the axonal signal that drives
the entire Schwann cell lineage, including myelination, is
an important milestone that will facilitate elucidation of
the mechanisms that underlie the morphogenetic and
transcriptional events of myelination. In the PNS, important remaining questions include how NRG1-dependent
activation of PtdIns 3-kinase initially promotes proliferation but later drives differentiation of Schwann cells, how
NRG1 signaling strength regulates the binary choice of
Schwann cell phenotypes, what limits NRG1 signaling
once myelination is complete, and whether perturbations
of NRG1 signaling contribute to neuropathology. Future
studies should also clarify the role of NRG1, and related
genes, in CNS myelination, including the question of
whether these axonal factors limit the efficacy of remyelination in the adult brain. Finally, the temporal and
quantitative control of NRG1 expression by neurons
remains to be explored. Elucidating these questions promises to provide important insights into the role of axon–
glial signaling in demyelinating disease and myelin repair.
Acknowledgements
Owing to space limitations, we regret any omissions in citing other relevant
publications. We thank C Birchmeier, D Falls, C Lai, J Loeb, M Schwab,
and C Taveggia for insightful discussions and for comments on the
manuscript. Work from the authors’ laboratories cited in this review has
been supported by grants from the Duetsche Forschungsgemeinschaft
(Center for the Molecular Physiology of the Brain), National Institutes of
Health, and the National Multiple Sclerosis Society.
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