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First published online March 20, 2009
doi: 10.1242/10.1242/dev.022418
Review |
Institute of Cell Biology, ZMBE, University of Münster, Von-Esmarch-Straße 56, 48149 Münster, Germany.
* Author for correspondence (e-mail: erez.raz{at}uni-muenster.de)
SUMMARY
Chemokines and their receptors were discovered about twenty years ago as mediators of leukocyte traffic. Over the past decade, functional studies of these molecules have revealed their importance for cell migration processes during embryogenesis, which, in addition to providing mechanistic insights into embryonic development, could complement information about chemokine function in the immune system. Here, we review the roles of the chemokine stromal cell-derived factor 1 (SDF-1/CXCL12) and its receptor CXCR4 during zebrafish and mouse embryonic development, and discuss their function in regulating the interactions of cells with their extracellular environment, in directing their migration, and in maintaining their location.
Introduction
Chemokines (chemotactic cytokines) are a group of vertebrate-specific small
(8-14 kDa) proteins that, depending on the presence and the position of
conserved cysteine residues, are categorized into four subgroups (C, CC, CXC
and CX3C). The chemokines (of which there are at least 46 in humans) interact
with a smaller number of G-protein-coupled seven-transmembrane receptors (of
which there are at least 18 in humans)
(DeVries et al., 2006
;
Zlotnik et al., 2006). These
chemokine receptors are classified based upon the type of chemokines they bind
to; their name includes the letter `R' and a number that signifies the
chronological order in which they were identified. The best-characterized role
of chemokines is in the control of cell trafficking and activation as part of
the immune response (Luster,
1998), where they direct the movement of responsive cells towards
higher concentrations of their ligand in the environment (a process termed
chemotaxis). This function is shared by practically all members of the
chemokine superfamily.
Chemokines can be classified into two groups: inflammatory chemokines,
which recruit leukocytes to inflamed tissues; and homeostatic chemokines,
which are constitutively produced and control homeostatic leukocyte traffic,
secondary lymphoid organ structure and processes not related to the immune
system. Chemokines and their receptors have attracted special attention in
recent years as they are involved in a range of clinical disorders, such as
Human immunodeficiency virus (HIV) infection, autoimmune conditions,
inflammatory diseases and cancer, making them attractive potential targets for
drug development (Viola and Luster,
2008; Zlotnik,
2008).
Whereas the primary role of chemokines is in the immune system, the
homeostatic chemokine SDF-1/CXCL12 and its receptors CXCR4 and CXCR7 have been
found to play crucial roles in a wide range of developmental processes. The
first evidence that chemokines have a function beyond the control of leukocyte
trafficking was obtained from the analysis of mice in which
Sdf-1/Cxcl12 or its receptor Cxcr4 were knocked out,
resulting in disturbed vascular development, hematopoiesis and cardiogenesis
(Nagasawa et al., 1996;
Tachibana et al., 1998;
Zou et al., 1998). These
findings, and subsequent in vivo and in vitro studies in mice, fish and chick,
have expanded our knowledge of the biological significance of chemokines, and
have demonstrated their roles in muscle patterning, heart development,
melanophore patterning, blood vessel formation, neuronal patterning and
neurotransmission, cell migration in embryogenesis, and the homing of
hematopoietic cells during ontogeny (Chong
et al., 2007; Horuk et al.,
1997; Knaut et al.,
2005; Nagasawa et al.,
1996; Sparmann and Bar-Sagi,
2004; Svetic et al.,
2007; Vasyutina et al.,
2005; Ara et al.,
2003b; David et al.,
2002; Doitsidou et al.,
2002; Herpin et al.,
2008; Hesselgesser et al.,
1998; Knaut et al.,
2003; Limatola et al.,
2000; Nair and Schilling,
2008; Sasado et al.,
2008; Stebler et al.,
2004). In this review, we discuss several examples of the roles
that SDF-1/CXCL12 and its receptors play in early development. As results
concerning the role of chemokines in mouse embryonic development have been
recently reviewed elsewhere (Cardona et
al., 2008; Li and Ransohoff,
2008; Tiveron and Cremer,
2008), we discuss them only briefly here and focus instead on
recent studies of chemokine signaling in zebrafish embryogenesis.
The optical clarity and extra-uterine development, combined with its genetic tractability, make the zebrafish an excellent model for studying chemokine-dependent cellular and developmental processes at an unprecedented resolution. As we review here, these characteristics have enabled studies of the function of CXCL12 proteins (as a result of gene duplication, zebrafish possess two CXCL12-encoding genes, cxcl12a and cxcl12b) and their receptors (CXCR4a, CXCR4b and CXCR7b in zebrafish) in controlling the migration of cells during gastrulation, primordial germ cell (PGC) migration, and the migration of cell clusters during the development of the zebrafish lateral line organ.
Controlling cell interactions with the extracellular environment
A central theme in inflammation and immunity is leukocyte extravasation,
the movement of leukocytes out of the circulatory system during normal immune
surveillance or in the course of responses to local tissue damage or
infection. The recruitment of leukocytes to specific sites in the body
involves the function of adhesion molecules (such as selectins) and their
ligands, as well as that of chemokines and their receptors (for reviews, see
Alon and Dustin, 2007;
Ley et al., 2007). The
signaling cascade that leads to leukocyte recruitment is initiated by
selectin-mediated adhesive interactions of the leukocytes with endothelial
cells at regions where extravasation should occur. These interactions tether
the circulating cells to the blood vessel wall, facilitating the firmer
attachment of the leukocytes to these sites. The increased cell-extracellular
matrix (ECM) adhesion in these locations is mediated by integrins, ECM
receptors that are activated by chemokine signaling.
|
;
Nair and Schilling, 2008), in
which the roles of the chemokine receptor CXCR4a and the ligand CXCL12b were
investigated (Fig. 1).
The position of mesodermal and endodermal cells in the embryo is determined
by the coordinated movement of these germ layers during gastrulation. The
coordination between endoderm and mesoderm migration thus controls the proper
location and morphology of the tissues and organs that develop from these germ
layers. During gastrulation, cxcl12b is expressed in mesodermal
cells, whereas cxcr4a is expressed in the endodermal cell layer. By
analyzing zebrafish embryos deficient for the function of this chemokine and
chemokine receptor, Nair and Schilling discovered that severe defects in
endodermal organ development occur in their absence, including pancreas, liver
and intestine duplications (Nair and
Schilling, 2008). In their investigation of the underlying basis
of these defects, the authors observed that the function of CXCR4a and CXCL12b
is required to coordinate the movement of endodermal cells with that of the
mesodermal germ layer (Fig.
1A). Specifically, the lack of CXCL12b-CXCR4a signaling resulted
in the `untethering' of the endodermal layer such that it was displaced
towards the animal pole of the embryo relative to the mesodermal germ layer
(Fig. 1B,C).
Nair and Schilling went on to show that the `tethering' of endodermal cells
requires CXCR4a-dependent integrin β1 function. The suggested course of
events is thus that maternally and mesodermally provided CXCL12b activates the
CXCR4a receptor, which in turn enhances integrin-dependent endodermal cell
adhesion to the extracellular matrix. In this instance, the precise mechanism
by which the activation of the chemokine receptor leads to an increase in
integrin β1 function is not known, but could involve transcriptional
activation of this gene (Nair and
Schilling, 2008). It would be interesting to determine whether the
activation of integrin function also occurs at the protein level, in which
case endodermal cell migration would constitute an accessible model for
studying certain events in leukocyte extravasation.
Directing cell migration
The importance of chemokines for in vivo chemotaxis was first shown in the
context of the immune system, in relation to the accumulation of lymphocytes
at sites of immune and inflammatory reactions (reviewed by
Baggiolini, 1998). The first
chemokines to which lymphocytes were reported to respond with chemotactic
activity were RANTES (CCL5), MIP-1
(CCL3) and MIP-1β (CCL4)
(Baggiolini et al., 1994). A
subsequent wave of studies established that chemokines play a role in numerous
cell trafficking events in the immune system (reviewed by
Sallusto and Baggiolini,
2008).
Consistent with the in vitro and in vivo activity of chemokines within the
immune system, chemokines were found to guide cell migration in vivo during
development and disease. For example, the distinctive metastatic pattern of
breast cancer has been suggested to involve the attraction of CXCR4-expressing
tumor cells to organs in which CXCL12 is found, such as the lung, liver and
bone marrow (Muller et al.,
2001). During normal brain development in mouse, the migration of
cortical interneurons is controlled by CXCL12
(Stumm et al., 2003;
Tiveron et al., 2006). In this
setting, the interneurons follow stereotypic migration routes in the cortex,
along which Cxcl12 RNA is expressed, suggesting that this chemokine
prefigures the route of cell migration. Similarly, CXCL12 was shown to act as
a chemoattractant for cortical neurons
(Stumm et al., 2003). The
proper migration of these cells in vivo depends on CXCR4 function, as revealed
by the analysis of mice that lack the normal expression of either
Cxcr4 or Cxcl12 RNA
(Stumm et al., 2003;
Tiveron et al., 2006).
One of the best-characterized examples of chemokine-guided single-cell
migration in development is that of PGCs in fish, mouse and chick
(Ara et al., 2003a;
Doitsidou et al., 2002;
Herpin et al., 2008;
Knaut et al., 2003;
Molyneaux et al., 2003;
Stebler et al., 2004). In
zebrafish, the process by which CXCR4b-expressing germ cells
(Doitsidou et al., 2002;
Knaut et al., 2003) arrive at
their target - the position where the gonad develops - is regulated by the
ligand-receptor pair CXCL12a-CXCR4b
(Doitsidou et al., 2002), a
combination distinct from the CXCL12b-CXCR4a pair that is required for the
process of endoderm tethering mentioned above. CXCL12a is expressed in tissues
that serve as the PGC migration targets, and both CXCL12a and its receptor
CXCR4b were shown to be essential for the normal migration of these cells
(Fig. 2A-C)
(Doitsidou et al., 2002;
Knaut et al., 2003).
Specifically, in embryos that lack the activity of either CXCL12a or CXCR4b,
the PGCs failed to migrate directionally towards their targets
(Fig. 2B,C). Consistently,
cells engineered to express CXCL12a readily attract CXCR4b-expressing PGCs,
supporting the notion that CXCL12a constitutes the actual guidance cue for
these cells (Blaser et al.,
2005). Interestingly, the CXCL12-CXCR4 axis has been found to play
a role in controlling PGC migration in other organisms as well. A correlation
between the expression pattern of CXCL12 and the migration path of PGCs has
also been demonstrated in mouse, chick and medaka
(Herpin et al., 2008;
Molyneaux et al., 2003;
Stebler et al., 2004).
Furthermore, CXCL12 is capable of influencing the migration path of PGCs (in
the cases of mouse and chick), and reducing the function of the receptor or
its ligand results in abnormal cell migration (in the cases of mouse and
medaka).
|
; Burns et al.,
2006; Thelen and Thelen,
2008). Surprisingly, whereas knocking down CXCR7b in zebrafish
embryos resulted in a strong PGC migration phenotype
(Fig. 2D), cxcr7b RNA
was not visibly expressed in the PGCs, unlike cxcr4b RNA, nor was it
required for the mobilization of calcium, a general second messenger in
chemokine receptor signaling (Boldajipour
et al., 2008). These observations are consistent with the features
attributed to decoy receptors - receptors that merely bind their ligand
without inducing downstream signaling
(Mantovani et al., 2006).
Indeed, CXCR7b was shown to be dynamically expressed in various somatic
tissues and to function as a sink for CXCL12a. This conclusion was based on
the observation that CXCR7b-expressing cells exhibit strong CXCL12a
internalization activity and on the fact that PGCs show reduced active
migration and polarization in a CXCR7b-depleted environment
(Boldajipour et al., 2008).
This cellular response is in agreement with the idea that, in the absence of
CXCR7b, CXCL12a levels are significantly increased, thus interfering with the
formation of an informative chemotactic gradient
(Fig. 2D). The finding that
Cxcl12a mRNA levels are controlled by microRNAs
(Giraldez et al., 2006)
suggests that the restriction of CXCL12a production by controlling RNA
stability and translation could represent yet another mechanism for regulating
the shape of the CXCL12a gradient.
The CXCL12a-CXCR4b ligand-receptor pair has been shown to coordinate not
only single cell migration, but also that of cells moving as a cluster.
Collective cell migration, defined as the migration of cells that maintain
cell-cell interactions during their movement, is a common theme in
morphogenesis and disease (Friedl et al.,
2004; Friedl and Wolf,
2008; Lecaudey and Gilmour,
2006). The invasion of solid tumors, such as human fibrosarcoma,
into their surrounding tissue also involves the formation of multicellular
strands. The migration of such strands is pioneered by cells (cancer cells or
activated fibroblasts) at the front of the strand that are followed by tumor
cells that maintain cell-cell contact
(Friedl et al., 2004;
Friedl and Wolf, 2008;
Gaggioli et al., 2007;
Wolf et al., 2007). Examples
of collective cell migration in normal development include branching
morphogenesis for duct formation (e.g. in Drosophila tracheal
development), border cell migration (during Drosophila oogenesis),
and morphogenetic movements during early embryonic development, such as
convergence-extension movements in vertebrate gastrulation
(Affolter and Caussinus, 2008;
Montell, 2006;
Rohde and Heisenberg, 2007;
Rorth, 2007;
Solnica-Krezel, 2005).
In the zebrafish, the collective migration of a group of cells called the
posterior lateral line primordium (PLLP) has been shown to require
CXCL12a-CXCR4b signaling (David et al.,
2002; Ghysen and
Dambly-Chaudiere, 2007; Haas
and Gilmour, 2006) (Fig.
3A-C). The PLLP is a cohesive mass of approximately 100 cells that
migrates from the anterior to the posterior of the embryo along a path defined
by the expression of the chemokine CXCL12a
(Ghysen and Dambly-Chaudiere,
2007). As was clearly demonstrated by knockdown experiments and
mutant analysis, CXCR4b function is required for the movement of the
primordium along the path defined by CXCL12a
(David et al., 2002;
Haas and Gilmour, 2006).
However, this description of the system does not provide a mechanistic
explanation for the observed directionality of PLLP migration through the
embryo. Specifically, the transcription of cxcl12a is not polarized
along the migration axis and thus cannot provide the required positional
information pattern by itself (David et
al., 2002). The migration of the primordium can, however, be
guided experimentally by an ectopic CXCL12a source, or by CXCL12a expressed in
other tissues of the embryo (Haas and
Gilmour, 2006; Li et al.,
2004), suggesting that directional migration does involve CXCR4
signaling. Very intriguing is the observation that the PLLP can, under certain
experimental conditions, migrate in the opposite direction (from the posterior
to the anterior) along the CXCL12a path, hence suggesting that polar migration
is directed by the organization of the primordium itself, rather than by the
polarized production of chemokines in the environment
(Haas and Gilmour, 2006).
|
; Valentin et al.,
2007). This expression pattern appears to be dictated by
Wnt/β-catenin and FGF signaling (Aman
and Piotrowski, 2008), and might involve antagonistic interactions
between the two receptors
(Dambly-Chaudiere et al.,
2007) that together result in the observed polarity in the
expression of the two molecules. The functional significance of these
observations lies in the suggestion that, as a non-signaling receptor, CXCR7b
expression at the back of the cell cluster is responsible for sequestering
CXCL12a, thereby generating an effective gradient of the chemokine across the
PLLP (Dambly-Chaudiere et al.,
2007; Ghysen and
Dambly-Chaudiere, 2007) (Fig.
3D). This hypothesis, which is in line with the suggested role for
CXCR7b in controlling PGC migration as discussed above
(Boldajipour et al., 2008),
can account for the behavior of the cluster in wild-type, as well as in
manipulated or mutated, zebrafish embryos. It would be interesting to
determine whether in other examples of collective migration a similar strategy
is in place to generate an intrinsic chemotactic gradient in an otherwise
uniform attractant field.
In contrast to the examples mentioned above, the precise role of CXCR7 in
additional CXCR7-dependent processes, such as cardiac development,
vasculogenesis and angiogenesis in mouse or PGC and PLLP migration in medaka
(Miao et al., 2007;
Sasado et al., 2008;
Sierro et al., 2007), is not
known. It would be interesting to determine whether CXCR7 acts as a decoy
receptor that controls the distribution of its ligands in these cases as
well.
Keeping cells in place
An interesting variation on the theme of chemokine function in directing
cell movement occurs when a chemokine gradient appears to instruct cells to
maintain their position. In contrast to their role in coordinating the
migration speed of one tissue relative to another population of moving cells
(e.g. during zebrafish gastrulation, see
Fig. 1), chemokines can be
engaged in anchoring cells at a certain stationary position within a
developing tissue. This specific function of chemokines was revealed in an
analysis of the multiple roles that CXCR4 and CXCL12 play in the development
of various mouse brain structures (Cardona
et al., 2008; Li and
Ransohoff, 2008; Tiveron and
Cremer, 2008). The first migration process in the brain shown to
depend on CXCL12-CXCR4 signaling was the migration of small neurons called
granule cells in the mouse cerebellum (Fig.
4A-C) (Ma et al.,
1998; Zou et al.,
1998). Interestingly, in the cerebellum of Cxcl12- or
Cxc4r-deficient mice (Fig.
4B,C), cells from the external granular layer (EGL, an external
cell layer of the cerebellum) migrate prematurely into more internal layers of
the cerebellum. The analysis of the CXCL12 and CXCR4 expression patterns, and
of the effect of CXCL12 on granule cells, has uncovered the basis of this
phenotype (Reiss et al., 2002;
Zhu et al., 2002). These
studies have shown that CXCL12 serves as an attractant for neuronal cells at
the EGL. CXCL12 is provided to the granule cells by meningeal cells that are
located at external parts of the cerebellum, thereby anchoring granule cells
close to the brain surface. Intriguingly, in the later (postnatal) stages of
mouse cerebellar development, the migration of granule cells away from the
CXCL12-expressing peripheral layer correlates with the loss of CXCR4
expression from the surface of the migrating cells. An analogous role for
CXCL12-CXCR4 signaling in anchoring cells to a specific location in the brain
has been demonstrated for other cell types. For example, the Cajal-Retzius
cells of the marginal zone in the developing brain require CXCL12 signaling to
prevent them from being displaced into deeper cortical layers
(Paredes et al., 2006;
Tiveron and Cremer, 2008).
|
;
Doitsidou et al., 2002;
Knaut et al., 2003;
Molyneaux et al., 2003;
Stebler et al., 2004). These
findings are consistent with the idea that the CXCR4-expressing PGCs are
retained at their location at the target site through the influence of CXCL12.
To confirm this possibility would require observing the response of PGCs to
the loss of the chemokine receptor or ligand function after PGCs arrive at
their target site, which remains a technical challenge. Nevertheless, it is
worth noting that high-resolution analysis of cell behavior at the site of the
gonad supports this proposition. Specifically, the examination of zebrafish
PGCs when clustered at their target site, where peak levels of CXCL12 are
expressed, has revealed that the cells extend small protrusions in all
directions and remain in this location
(Reichman-Fried et al., 2004).
Indeed, the cessation of PGC migration upon their arrival at the target site
can be experimentally recapitulated by generating CXCL12-rich ectopic domains
within the zebrafish embryo, which retain the PGCs that reach these domains
(Reichman-Fried et al.,
2004).
The involvement of chemokines in controlling the positioning of cells at a
specific location emerges as a common theme in both normal and disease
contexts. For example, human and murine hematopoietic stem cells (HSCs) are
maintained in the bone marrow through CXCL12-CXCR4 interactions
(Petit et al., 2002). The
reduction of CXCL12 levels in the bone marrow of mice or humans by granulocyte
colony-stimulating factor (G-CSF) treatment, coupled with an increase in CXCR4
expression and maintenance of CXCL12 levels in the blood, results in HSCs
becoming mobilized and entering the blood stream. The role of the CXCL12-CXCR4
signaling pathway in regulating cell compartmentalization has been further
demonstrated by knocking out CXCR4 function selectively in mouse B cell
precursors (Nie et al., 2004).
Cxcr4-deficient B cell precursors were shown to migrate out of their
normal niches in the bone marrow prematurely. Similar results were obtained
when studying certain pathological conditions. For example, the bias of
certain malignancies to metastasize to specific distant organs suggests that,
in addition to the directed migration of tumor cells (as discussed in the
previous section), the microenvironment within the target organ might assist
the establishment of metastases at these locations
(Ben-Baruch, 2008).
Interestingly, various parameters important for the formation of tumors at
metastatic sites were shown to depend on inflammatory and homeostatic
chemokines and their receptors (Ben-Baruch,
2006; Ben-Baruch,
2008; O'Hayre et al.,
2008). For example, the homing of metastatic cells, the
infiltration of tumor-associated macrophages that can support the tumor by
providing growth factors and inhibiting the anti-tumor immune response, the
regulation of angiogenesis at the tumor milieu, tumor cell proliferation and
tumor cell malignancy are all positively regulated by chemokines.
Conclusions
Chemokines appear to function in two main modes: they can either provide
positional information in the form of a gradient or act as a switch that is
responsible for changing certain cellular properties. Chemokine gradients can
be experimentally generated in vitro and in vivo, and they effectively direct
the migration of cells that express the proper receptors (e.g.
Blaser et al., 2005;
Bleul et al., 1996;
Doitsidou et al., 2002;
Knaut et al., 2003). Such
gradients are postulated to form and function in the intact developing
organism; for example, during the migration of cells towards their targets,
and in the retention of cells at one location after their arrival at their
migration target. In generating such positional information, the transcription
pattern of the RNA that encodes the chemokine normally plays a crucial role in
shaping the gradient, with the interesting possibility of gradient formation
at the posttranslational level through the action of CXCR7 within the
zebrafish PLLP (Ghysen and
Dambly-Chaudiere, 2007). The intracellular signaling pathways that
are responsible for the directional migration of cells towards domains of high
chemokine expression, or for maintaining cell location in such developmental
contexts, are poorly understood. PGC migration appears to involve the
polarization of intracellular calcium and the contraction of myosin, which
drive a specific type of cellular protrusions that are powered by the flow of
cytoplasm in the direction of migration (termed blebs)
(Blaser et al., 2006).
Chemokine-directed migration in the development of other morphologically
different cell types could, however, involve other biochemical pathways. In
these cases, one should examine the possible involvement of signaling cascades
that have previously been shown to control the migration of HSCs in mammals in
response to chemokine signaling (reviewed by
Thelen and Stein, 2008).
Specifically, molecules that control F-actin formation at the leading edge,
such as PI3K
, DOCK2 and RAC, and molecules involved in the remodeling
of the actin cytoskeleton, such as ARP2/3, formins, WASP and N-WASP, are among
the effectors that might play a role in cell polarization and migration in the
instances discussed above.
Another effect of chemokines on cell migration involves their control of
integrin-mediated adhesion (Ley et al.,
2007; Luo et al.,
2007). This effect is considered to be mediated by the rapid
modulation of the affinity of integrin receptors for their substrates through
a conformational change that requires the RAP1, talin and kindlin proteins
(Thelen and Stein, 2008), as
well as by alterations in the amount or distribution of integrin receptors on
the cell surface (Carman and Springer,
2003). The control of integrin-mediated cell adhesion by
chemokines does not depend on graded chemokine distribution, but leads to an
increased interaction or tethering of the responding cells with their
environment. Similarly, CXCL12b, the signal that controls the tethering of
zebrafish endodermal cells to the mesodermal cell layer, is initially provided
in the form of uniformly distributed RNA
(Nair and Schilling, 2008) and
could thus function in a gradient-independent manner. Whereas chemokines can
induce extremely rapid (subsecond) changes in integrin activity in the context
of leukocyte adhesion to ensure cell arrest under flow conditions at sites
where the cells transmigrate into the vascular system, developmental pathways
might not require such fast reaction times. Consistently, the
CXCL12b-CXCR4a-mediated control of zebrafish endodermal cell adhesion is
associated with changes in integrin transcription levels, which represents a
slow response to chemokine signaling.
Over the past decade, and particularly during the last few years, we have witnessed an impressive increase in the number of migration processes in development and disease that have been shown to be controlled by chemokines. Interestingly, whereas the cell types and the tissue contexts differ, the roles that chemokines play in the immune system and in development are remarkably similar on a conceptual level. Therefore, attempts to find answers to open questions that concern the mechanisms of chemokine gradient formation, the intracellular events that translate the chemokine gradient into directed migration and the processes by which chemokines control integrin-mediated cell adhesion will benefit from combining the insights gained in these two disciplines.
Footnotes
We thank Michal Reichman-Fried for comments on the manuscript. We are supported by funds from the German Research Foundation (DFG), the Max Planck Society (MPG) and the Medical Faculty of the University of Münster.
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