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Seminars in Cell & Developmental Biology 55 (2016) 111–118
Contents lists available at ScienceDirect
Seminars in Cell & Developmental Biology
journal homepage: www.elsevier.com/locate/semcdb
Review
Chemotaxis during neural crest migration
Adam Shellard, Roberto Mayor ∗
Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK
a r t i c l e
i n f o
Article history:
Received 21 December 2015
Accepted 22 January 2016
Available online 25 January 2016
Keywords:
Chemotaxis
Neural crest
Collective migration
SDF1/CXCL12
VEGF
C3/C3aR
a b s t r a c t
Chemotaxis refers to the directional migration of cells towards external, soluble factors along their gradients. It is a process that is used by many different cell types during development for tissue organisation
and the formation of embryonic structures, as well as disease like cancer metastasis. The neural crest (NC)
is a multipotent, highly migratory cell population that contribute to a range of tissues. It has been hypothesised that NC migration, at least in part, is reliant on chemotactic signals. This review will explore the
current evidence for proposed chemoattractants of NC cells, and outline mechanisms for the chemotactic
response of the NC to them.
© 2016 Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
Chemotaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
1.1.
Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
1.2.
Criteria to define a chemoattractant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
The neural crest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
2.1.
Neural crest formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
2.2.
Neural crest derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Neural crest migration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112
3.1.
Neural crest streams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3.2.
Collective migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
3.3.
Directional migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Neural crest long-range chemoattractants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
4.1.
Stromal cell-derived factor 1 (SDF-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
4.2.
Vascular endothelial growth factor (VEGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
4.3.
Fibroblast growth factor (FGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
4.4.
Platelet-derived growth factor (PDGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Neural crest short-range chemoattractants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
5.1.
Chase and run . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
5.2.
Co-attraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
∗ Corresponding author.
E-mail address: r.mayor@ucl.ac.uk (R. Mayor).
http://dx.doi.org/10.1016/j.semcdb.2016.01.031
1084-9521/© 2016 Elsevier Ltd. All rights reserved.
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A. Shellard, R. Mayor / Seminars in Cell & Developmental Biology 55 (2016) 111–118
1. Chemotaxis
1.1. Definition
Cell migration is fundamental to many processes in development and disease, including embryonic morphogenesis, wound
healing and the immune response [1]. This often involves cells
responding to specific signals that guide their movement, either
from mechanical stimuli, molecules bound to the extracellular matrix or soluble external factors [2–8]. Cell migration in
response to gradients of the latter, called chemotaxis, has been
widely studied and it is a well-established mechanism that provides directionality and persistence to migrating cells [7,9,10]. The
chemotactic response of cells, in part, involves the polymerisation
of actin at the leading edge and the accompanying formation of
protrusions, and myosin-II-mediated contraction at the rear [11].
1.2. Criteria to define a chemoattractant
The first description of chemotaxis was made by Engelmann and
Pfeffer in bacteria over a century ago [12,13]. Since then, repulsive [14,15] and attractive cues have been found for a variety
of processes [1,9]. However, most factors are multifunctional on
cell behaviour, which makes definitive demonstration of chemoattractant behaviour in vivo difficult. Nevertheless, some attributes
of chemoattractants may be summarised as follows. Chemoattractants are generally transcribed, translated and secreted by
the target tissue itself to where the responsive cells are migrating. These responding cells are required to express a receptor
for the chemoattractant when temporally appropriate. Loss of the
chemoattractant or its receptor should lead to failure of cells reaching the target region; instead, non-directional migration can be
expected. In vitro, localised chemoattractants should cause chemotaxis and in vivo, cells should be diverted from their normal path by
ectopic, localised sources of chemoattractant. Chemotaxis should
be rescued by an exogenous ligand when the endogenous chemoattractant is lost, if placed into the region the cells would normal
migrate toward. Chemotaxis requires that cells migrate up a concentration gradient of a soluble factor, so sufficient and consistent
changes in the chemoattractant’s concentration should be found
to give rise to a detectable gradient. This last point is perhaps the
most difficult to demonstrate due to technical limitations and that
in some cases the gradient is generated in situ by the migrating
cell [16]. Nonetheless, a fulfilment of these criteria is important
to show that not only are the cells capable of being chemotactic
towards the factor, but also that chemotaxis is actually happening
in vivo. Altered migration in response to the external factor would
otherwise demonstrate chemokinesis, the process by which factors
simply promote or support migration, rather than providing directionality to the movement as in the case of chemotaxis, as seen
in various cell types in physiology and throughout development
[9,11].
2. The neural crest
2.1. Neural crest formation
The neural crest (NC) is a transient cell population exclusively
found in vertebrates. It is initially induced at the neural plate border
as a result of the interaction between the ectodermal neural plate
and the epidermis [17]. Changes in the structure of the neural plate
cells cause fusion of the neural folds, resulting in the formation of
a closed neural tube and of NC on its dorsolateral aspect on each
side [17,18]. Both the prospective neural plate and the prospective epidermis contribute to the NC [19,20]. After induction, NC
cells undergo an epithelial-to-mesenchymal transition (EMT) [21],
in which cells acquire motility, epithelial polarity is lost and there is
a switch from more adhesive to weaker cadherin expression. These
and the accompanying cytoskeletal changes mean that the NC cells
leave the neuroepithelium of the dorsal neural tube and become
highly migratory [18].
2.2. Neural crest derivatives
The NC are multipotent stem cells, able to differentiate into
many cell types and extensively contribute numerous tissues
(Fig. 1A) [22]. NC cells receive inductive signals from the neural tube, paraxial mesoderm and the overlying ectoderm as they
migrate [23]. Their specification is a multistep process; their
fate is based on these paracrine signals, as well as the time at
which they migrate, their origin and the stream in which they
are found [23–27]. The cranial NC contributes to the craniofacial
mesenchyme, which includes cartilage, bone, teeth, cranial neurons, glia and connective tissue. Cardiac NC contributes to the
cardiovascular system, developing into melanocytes, cartilage, connective tissue and pharyngeal arch neurons. Trunk NC gives rise
to melanocytes, glia and neurons of the peripheral nervous system
and epinephrine-producing cells of the adrenal gland. The vagal and
sacral NC develops into the ganglia of the enteric nervous system
and sympathetic ganglia.
3. Neural crest migration
3.1. Neural crest streams
After undergoing EMT, the NC becomes a highly migratory
cell population, often likened to invasive cancers [18,28,29]. NC
cell migration has been studied in a variety of vertebrate animal
models, including Xenopus, zebrafish, chick, mouse [30] and even
non-classical model organisms such as lamprey [31], hagfish [32]
and turtle [33,34]. The NC migrate ventrally down the embryo,
initially as a continuous wave away from the neural tube, but
quickly splitting into discrete streams along stereotypical pathways to various sites (Fig. 1A). The cranial NC migrates along
dorsolateral routes between the ectoderm and underlying paraxial mesoderm [35,36]. In chick and mouse, early trunk NC migrates
ventrolaterally through the anterior sclerotome [37–40]. Trunk NC
migrating later, which will become melanocytes, follow the dorsolateral path between the dermomyotome and dorsal ectoderm,
with their migration affected by the structure of the somites [41].
However in zebrafish and Xenopus, melanocytes use both ventromedial and dorsolateral pathways [42,43].
The cranial NC divide into three streams that invade the segmented branchial arches (BAs), due to, at least in part, the repulsive
signals of ephrins and class 3 semaphorins (Fig. 1B). Eph/ephrin
signalling prevents NC cells from invading non-NC tissue and the
caudal half of somites, thereby restricting them to the rostral half
of somites in chick embryos [44,45]. Likewise, class 3 semaphorins
contribute to NC segregation in the head, trunk and caudal regions
of the sclerotome [46–51] by acting through plexin–neuropilin
complexes expressed by the NC [47–49,51]. The mixing of NC from
different streams is also prohibited because NC belonging to different streams express complementary Eph receptors and ephrin
ligands [35].
3.2. Collective migration
NC displays a range of migratory behaviours depending on
species and location within the embryo. Some exhibit a more individual migratory behaviour [52], whereas most of NC cells migrate
together, either as chains, groups or even single sheets, in spite
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113
Fig. 1. (A) Migration routes of the NC (green) in a representative vertebrate embryo. D, diencephalon; M, mesencephalon; R, rhombomere; OV, otic vesicle; BA, branchial
arch; red squares, somites. Below, examples of some of the cell types to which NC differentiate. (B) Representation of NC migrating in a cephalic stream. NC cells migrate
in distinct streams, mostly as a collective. Lateral migration is restricted by inhibitory signals at the borders (blue). Directional migration is an emergent property from CIL,
whereby Rho (orange) is upregulated at sites of N-Cadherin-based contact (red) between cells; only leaders can generate Rac-dependent protrusions (purple). This leads to
a polarised group of NC cells. Migration is inefficient by individual cells because polarity is not generated by CIL, a process dependent on cell interactions.
of the fact that NC go through EMT [1,29,53–55]. For example,
cephalic NC maintain short and long-range cell–cell interactions
during migration both in vitro [56] and in vivo [57–59]. This kind
of movement has been called collective cell migration, which can
be defined as the coordinated migration of cells as tight clusters
or loose groups (as in the case of NC), where cooperation between
cells contributes to their overall directionality [18,53,60–63]. Overall directionality during collective cell migration is higher than
during single cell migration, indicating that intercellular interactions promote the directionality of migrating NC [57–59]. Unlike
epithelial cells, which move slowly and have tightly formed intercellular adhesions, the collective mass of the mesenchymal NC is
a cohesive unit linked by transient contacts, such as N-Cadherin
adhesions [64–67]. N-Cadherin dynamics is regulated by lysophosphatidic acid receptor 2, prompting N-Cadherin endocytosis which
leads to an increase in tissue plasticity [68]. This plasticity allows
NC to migrate under physical constrains without abolishing cell
cooperation [68]. Moreover, semaphorin and ephrin inhibitory signals ensure NC remain in streams (see Section 3.1), and short-range
chemotaxis (see Section 5.2) promotes collectiveness of the group.
3.3. Directional migration
The importance of directional migration for the NC lies with
the fact that they must reach and populate specific target regions.
Directional migration requires cell polarisation, in order to specify a front that has localised actin polymerisation and a rear that is
able to contract [11,69]. Contact inhibition of locomotion (CIL), the
process by which contacting cells collapse their protrusions at the
site of contact and change their direction of migration [70,71], is
a mechanism that is able to polarize cells in a contact-dependent
manner [70,71]. NC exhibits CIL in vitro and in vivo [72]. The Rho
GTPases, Rac, Cdc42 and Rho, are important for cell polarisation
and cell migration [73]. Non-canonical (PCP) Wnt signalling is necessary for CIL in NC, by activating RhoA at sites of intercellular
contact, which in turn suppresses the generation and maintenance
of lamellipodia through its target ROCK [72,74]. The proteoglycan
syndecan-4, expressed by NC, cooperates with non-canonical Wnt
and N-Cadherin signalling to inhibit Rac activity at the cell–cell contact [74–76]. Together, mutually exclusive zones of Rac1 and RhoA
activity are generated in NC cells, meaning that protrusions are
formed only at sites where there is no NC–NC contact. Most NC cells
migrating in vivo maintain close proximity and move in compact
groups. Therefore, the polarity required for directional migration
is established because at the free edge of the cell cluster, due to
the lack of NC–NC contact, cells become polarized and generate
protrusions away from the group [77] (Fig. 1B, purple protrusions).
Hence, directional migration is an emergent property of NC cells
that depends on cell–cell interactions [78–80]. Importantly, it has
been shown that the pre-established polarisation of NC arising from
cell–cell contacts allows NC cells to respond to external chemoattractants more efficiently as a collective than as individual cells [81].
Consequently, NC chemotaxis becomes more efficient as cell density increases [81]. This collective interpretation of a chemotactic
gradient is referred to as collective chemotaxis, and it has been supported by mathematical modelling of collective cell migration [82].
However, CIL alone is not sufficient to explain directional migration,
as it would promote cell dispersion on its own. Significant evidence
supports the presence and requirement of chemoattractants for NC
migration in vitro and in vivo.
4. Neural crest long-range chemoattractants
Various chemoattractants have been proposed for the NC,
including SDF-1/CXCL12 [81,83–85], FGF [86–88], VEGF [89–92],
PDGF [93–95], SCF [96], NT-3 [97], GDNF [98–100], NRG1 [101]
and TGF␤ [102]. However, whether chemotaxis mediates the longrange directional migration of NC in vivo has not been conclusively
demonstrated. Chemoattractants do not seem necessary for directional migration in vitro and in silico, where it has been suggested
to be a self-organising property of the NC [81,82,103] as discussed
in Section 3.3. Furthermore, many NC cells begin migration prior to
full development of the target tissue and it is unclear how different NC subpopulations would be able to share common migratory
routes and invade different target regions using a limited number of chemoattractants. Conversely, some factors fill many of the
criteria discussed in Section 1.2, including appropriate expression
patterns and chemotactic behaviour of NC toward them. Here we
will examine the current evidence of the four most studied potential chemoattractants, which have the most convincing data.
4.1. Stromal cell-derived factor 1 (SDF-1)
SDF-1 (also named CXCL12) regulates many directional migration events during embryonic development, including migration
of the zebrafish posterior lateral line primordium (PLLp), primordial germ cells and various NC-derived cells [84,104–108].
In many model organisms, SDF-1 is expressed along the path
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taken by NC cells [83,84,101,109–111] that express the corresponding receptor, CXCR4 [83,84,111–114]. In some of these cases,
chemotactic activity of the NC to SDF-1 has not been properly tested, and how chemotaxis would be achieved in chick,
where SDF-1 is not found as a gradient, is unclear [109,110]. But
there are some examples of chemotaxis to SDF-1 that are supported by experimental evidence. For example, CXCR4-expressing
NC are chemotactic to SDF-1 in vitro [84,115] and SDF-1 misexpression diverts these NC cells away from their normal path,
causing major defects such as cardiovascular abnormalities in
many organisms [109,111,112,115–120], although mice NC behave
rather differently in that SDF-1 and CXCR4 mutants display only
mild abnormalities [121,122]. Perturbed SDF-1/CXCR4 signalling
disrupts NC cell migration [83,85,111,112], and some of the downstream components of this pathway have been identified. For
example, the GEF Ric-8A is required for NC chemotaxis to SDF-1
in vitro [123], but its mechanism of action is unclear. The regulation
of the CXCR4 receptor has also been shown to be important for NC
migration, as the transcription factor HIF-1␣ controls chemotaxis
to SDF-1 by regulating CXCR4 expression [124].
In Xenopus, cell–cell interactions are essential for the collective
chemotaxis of NC cells toward placodal-produced SDF-1 [81]. SDF1 is only able to stabilize cell polarity in cells already polarized
by cell–cell contacts, and therefore cannot attract non-polarized
individual NC cells [81]. Mathematical modelling has shown that
cell contact enhances the chemotactic response [125], consistent
with the experimental evidence that SDF-1 stabilises and amplifies cell protrusions promoted by cell contact [81], similar to the
chemotactic response of Drosophila border cells to EGFR and PVR
[126].
One major long-standing question is how NC segregates into
different regions to colonize and differentiate into distinct tissues
and organs. It has been proposed that different NC subpopulations
express different receptors [127]. Indeed, it has been shown that
differential response to SDF-1 and neuregulin by distinct NC subpopulations determines whether these cells will migrate into the
sympathetic ganglia or the dorsal root ganglia [101,111].
4.2. Vascular endothelial growth factor (VEGF)
By the onset of NC migration, VEGF is expressed in the head
ectoderm of avian embryos, specifically overlaying the dorsolateral migratory path of the rhombomeric 4 (r4) cranial NC,
which expresses its canonical receptor, VEGFR2, and co-receptor,
neuropilin-1 [89,128,129]. VEGF expression later extends to the
second branchial arch (BA2), and seems to be reduced in the onroute ectoderm [89]. During the initial stages of migration, VEGF
is uniformly expressed in the overlying ectoderm, rather than as a
gradient [89]. Nonetheless, both VEGFR2 and neuropilin-1 receptors are required for VEGF-mediated migration to BA2 [90,92].
In vitro, cranial NC are attracted to BA2 and VEGF [89] and in vivo,
r4 NC can be diverted from their normal path by ectopic VEGF
[89,91]. Perturbed VEGF/VEGFR2/neuropilin-1 signalling does not
affect directional migration toward the BA2 entrance, but prevents
invasion of BA2 at later stages [89,92,129].
It is not clear how VEGF can control directional NC migration,
as no VEGF gradient has been demonstrated so far. A mathematical
model of NC migration has proposed that the VEGF signal is diluted
through the proliferation of NC cells which self-generate a VEGF
gradient by the endocytosis of the ligand (Fig. 2A) [130]. This model
posits that only leader cells respond to VEGF, whereas trailing cells
respond to a second, unknown signal produced by leader cells [130].
However, a recent publication suggests that trailing cells can indeed
respond to VEGF [91]. Moreover, there are key assumptions that are
still awaiting experimental evidence: the consumption of VEGFA,
the short-range signals transmitted from leader to follower cells,
and the exclusive response of leader cells to VEGFA. It is unlikely
that the NC self-generate a gradient in mice, because murine NC
express VEGFA themselves [131].
4.3. Fibroblast growth factor (FGF)
FGF8 is expressed in the pharyngeal arch ectoderm and endoderm during NC migration through the arches [132,133] and it is
not expressed by the NC [134]. Its expression is partly dependent
on Notch in mouse, and on the presence of the NC cells themselves
in chick [86,135,136]. Migration of different NC populations to their
targets is dependent on FGF8 [133–135,137–139]. However, there
is varying evidence of chemotaxis between different NC subpopulations and species. In some cases, the NC have been shown to
express FGF8’s cognate receptors, FGFR1 and FGFR3, and there is
evidence that NC can be diverted from their usual paths by ectopic
FGF8 beads [86,87]. For other cases, there is only evidence that FGF8
is important for NC migration, but not for chemotaxis [137–139].
Species differences in NC migration can be illustrated in cardiac
development, where NC chemotaxis to FGF8 is critical for heart
development in chick and mouse [133,140,141], unlike in zebrafish
where FGF signalling is redundant for NC contribution to the heart
[139].
FGF2 has also been proposed as a chemoattractant for NC. FGF2 is
locally expressed and under the control of FGF8 in the mandibular
mesenchyme [88]. Mesencephalic mouse NC cells express FGFR1
and FGFR3, but although these NC are chemotactic to FGF in vitro,
there are no functional studies of FGF2 chemotaxis in vivo [88].
4.4. Platelet-derived growth factor (PDGF)
PDGFR␣ is expressed in the migrating NC of many species
[33,94,142–145] and in non-neuronal derivatives of the cranial
NC [140,144,146]. PDGFR␣ protein also localises to NC, although
its expression is not exclusive to NC and NC-derived tissues [95].
Patch heterozygotes, in which PDGFR␣ is deleted, have defects
in pigment cells derived from NC [147]. Patch homozygotes have
abnormalities suggestive of defective cardiac NC [148,149] and
PDGFR␣ mutants exhibit cleft palate, which results from failed
NC development [145,148,150]. PDGFR␣’s cognate ligands, PDGFA
and PDGFC, are found in the ectoderm, otic vesicle and pharyngeal
endoderm [94,143,146,151,152], which are NC targets. In mouse,
both PDGFR␣ and PDGFR␤ are required for the normal migration
of cardiac NC [153]. Although some NC derivatives are capable of
chemotaxis to PDGFA in vitro [146], which ligand is required for signalling through PDGFR␤, and whether it acts chemotactically on
NC cells in vivo, is unknown. Exogenously implanted PDGF-AA is
able to attract PDGFR␣-expressing NC in vivo [93–95]. In zebrafish,
it appears that PDGF-AA pre-localised to where the PDGFR␣expressing NC cells migrate [94]. Interestingly, the expression
pattern of a PDGFR␣ negative regulator, Mirn140, is identical to
PDGFR␣, and it has been proposed that this mechanism of PDGFR
signalling modulation mediates the chemotaxis of cranial NC to
the oral ectoderm, since overexpression of Mirn140 phenocopies
PDGFR␣ mutants [94].
In conclusion, although there is some evidence that suggest that
SDF-1, VEGF, PDGF and FGF could work as NC chemoattractants,
none of these molecules have been shown to be present in a gradient along the NC migratory pathways. Instead of precluding these
molecules to be classified as NC chemoattractant, the mechanism
to sense a chemoattractant could be more complex than simply
reading a long range gradient.
A. Shellard, R. Mayor / Seminars in Cell & Developmental Biology 55 (2016) 111–118
115
Fig. 2. Mechanisms of chemotaxis. (A) Proposed model for a NC self-generated gradient of VEGF (pink) from an initially uniform expression of VEGF in the overlying ectoderm.
VEGF is consumed by NC, potentially by its endocytosis when bound to VEGFR2/neuropilin-1 (purple). Leaders are able to respond to unconsumed VEGF in front, relaying
a signal to its followers. (B) NC undergo short-range chemotaxis to placodal cells (blue) via placodal-secreted SDF-1 (yellow) which binds CXCR4 (olive) on NC. CIL through
PCP signalling and a transient N-Cadherin adhesion mediates repulsion between NC and placodes, leading to the placode moving away (run) from the NC, while the NC still
follow (chase) the placode due to chemotaxis. This is referred to as ‘chase and run’. (C) NC co-attraction. NC co-expresses the chemoattractant C3a and its cognate receptor
C3aR. NC-produced C3a binds to C3aR on NC cells, causing activation of Rac. In this manner, C3a promotes cohesion of the NC cluster; cells that move away by CIL return to
the high concentration of C3a present in the cluster.
5. Neural crest short-range chemoattractants
5.1. Chase and run
Many examples of paracrine chemotaxis, to enhance migration
and for cell guidance, have been described in development and
cancer [54,56,105]. Xenopus and zebrafish NC cells, which express
CXCR4, also undergo paracrine chemotaxis in response to SDF-1
secreted by placodal cells in vitro [154]. Cranial placodes are thickened regions of ectoderm that contribute to the development of
cranial sensory structures [155]. Reciprocal interactions between
the NC and placodal cells are required for normal morphogenesis of both populations [155]. Mechanistically, contact inhibition
of locomotion (CIL) generates polarised NC [72] whose protrusions
are stabilised by SDF-1/CXCR4 which enhances and maintains the
polarity [81]. Upon contact with NC cells a transient but functional
N-Cadherin-based adhesion complex is formed between NC and
placodal cells [154]. Migratory NC explants normally generate traction forces around the edge [156], but at the point of N-Cadherin
engagement focal adhesions and protrusions are downregulated as
CIL is induced [154]. Consequently, NC repolarise and separate from
the placodal cells, whilst loss of focal adhesions and collapse of protrusions in the rear of the placode cluster causes the placodal cells
to move away from the NC. This process has been termed ‘chase
and run’ in which NC chase placodal cells by short-range chemotaxis, whereas the placode runs away from NC by CIL (Fig. 2B). The
bidirectional interactions between NC and placodal cells coordinate
highly efficient directional migration of both populations towards
lateral and ventral regions.
5.2. Co-attraction
Short-range chemotaxis may also maintain the cohesion of
groups of cells during migration, as suggested in cancer [157,158]
and demonstrated in Dictyostelium [11]. Despite having weak cell
adhesion complexes, most NC cells migrate collectively rather than
as individuals [29,54,58]. Short-range chemotaxis is used to maintain collectiveness in NC groups during directional migration. NC
cells produce the complement factor C3a, and express its receptor,
C3aR [159]. Therefore, high levels of C3a are found where NC cells
are abundant, and cells that lose contact with their neighbours are
able to migrate back to the group, following this chemotactic gradient. Mechanistically, C3a signalling leads to Rac1 activation which
is sufficient to polarise escaping NC back to the group (Fig. 2C)
[159]. This mechanism of short-range chemotaxis is termed coattraction. Co-attraction counterbalances CIL, which is required
for directional migration but promotes cell dispersion [72,159].
Accordingly, inhibition of C3 or its receptor reduces collectiveness,
as cells are forced apart by CIL [159]. C3a and C3aR have also been
found in cephalic NC cells in mouse (Lambris and Mayor, unpublished) and chick (Bronner and Mayor, unpublished), and in the
mesoderm of Xenopus embryos [160]. NC cell migration in zebrafish
and avian embryos also suggest a co-attractive behaviour, although
the molecular mechanisms have not yet been described. The importance of short-range chemotaxis to hold groups of cells together is
supported by mathematical models, where co-attraction and CIL
are necessary and sufficient for generating directional migration of
groups in confined streams [82,159].
6. Concluding remarks
Various molecules have been proposed as chemoattractants
for the NC, some of which have very strong evidence, such as
SDF-1 and VEGF [81,89]. However, some aspects of the criteria
required to unequivocally demonstrate chemoattractant activity
are still lacking. For example, convincing graded expression patterns have not been shown for any factors, and there is not
enough experimental evidence for various aspects of the proposed
model of self-generated chemotactic gradients. Nonetheless, novel
concepts have emerged from studies of NC chemotaxis, including collectiveness maintained by chemotaxis (co-attraction) [159],
directional migration of distinct cell populations based on shortrange chemotaxis (‘chase and run’) [154], collective chemotaxis
[81], and explanations of how differential response to chemotactic cues may achieve tissue organisation during development
[101,111]. Thanks to improved in vivo imaging techniques and the
development of genetic models, the future holds better prospects of
further assessing NC cell chemotaxis and dissecting the molecular
mechanisms involved [161,162].
116
A. Shellard, R. Mayor / Seminars in Cell & Developmental Biology 55 (2016) 111–118
Acknowledgements
We thank Isabel Bahm and Andras Szabo for comments on the
manuscript. Work in R.M. lab is supported by grants from MRC
(M010465 and J000655), BBSRC (M008517) and Wellcome Trust.
A.S. is a recipient of a Wellcome Trust PhD fellowship.
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