The significance of Wnt signaling for cell migration came into play most recently, and with it, a burst displaying the diversity of Wnt family members in signal transduction and physiological function. Our most comprehensive knowledge of how Wnt signaling controls cell movement becomes obvious in the gastrulation process of vertebrates. Here, the role of Wnt molecules in driving cell migration can be separated from their role in regulating cell differentiation. This discrimination is difficult to make for other migration processes, e.g., neural crest or myocyte migration. Therefore, the role of the different Wnt signaling cascades in gastrulation movements are covered in the main part of this article while other cell migration processes are touched only briefly.
Cell movements during gastrulation have been extensively studied in the amphibian, Xenopus laevis, taking advantage of the size of the embryo and its extracorporal development that allows manipulations and explant observations at very early stages of embryogenesis. Pionieering work in the creation of assays to study the different cell behaviors was contributed by Keller and Winklbauer.1,2,3 With these assays they were able to distinguish between the epiboly of the ectoderm, the active migration of the head mesoderm, the convergent extension movement of the involuting mesoderm and the rotation of the endoderm. Although gastrulation movements express species-specific characteristics, reflecting the topography of yolk and cytoplasm distribution in the egg, common patterns of cell behaviour are observed in different organisms and they are repeatedly used during morphogenesis of an individual. Convergent extension movements, for example, occur ubiquitously in metazoan development. They drive gastrulation but also elongation of the embryo in vertebrates, archenteron elongation in sea urchins, germ band extension and imaginal disc evagination in Drosophila. In all these cases, convergence and extension describe mass tissue movements based on narrowing and lengthening of cell populations. Therefore, it seems most likely that the regulative mechanisms inducing and controlling these cell behaviours are also conserved.
Different Wnt subfamily members seem to be involved in controlling gastrulation movement. At first view, the reports appear confusing as increase in Wnt signaling activity but also its inhibition result in disturbance of the migration process. This contradiction may be solved when the complex pattern of tissue movements is temporally and spatially sorted into the individual cell behaviours of the different tissue compartments.
A Moderate Wnt/PCP Signaling Drives Convergent Extension
The best example of contradictory observations is given by Wnt-11 which activates the Wnt/PCP (planar cell polarity) pathway (see chapters 1 and 6 in this issue). In Xenopus, either activation or inhibition of this pathway by exogenous expression of wildtype (wt) or mutants of the signaling molecule, its receptor or downstream effectors lead to gastrulation defects. 4-8 The induction of cell polarity is one of the first crucial steps in convergent extension movements as cells from both lateral sides of an embryo intercalate and migrate towards the dorsal midline (Fig. 1). Performing time-lapse studies with Xenopus open-face Keller explants Wallingford et al 6 were able to demonstrate the consequence of defect Wnt/PCP signaling on cellular level. Expression of the Xdsh mutant (Xdd1) or overexpression of wt Xdsh led to loss of cell polarity formation. The cells showed randomly distributed protrusive activity of high frequency, a behavior normally observed shortly before convergent extension starts (Fig. 2, time point 0). In controls, lamellopodia formation was mediolaterally biased and more stable reflecting the bipolar status (Fig. 2, time point 15–20). An influence of Wnt/β-catenin signaling could be excluded because dnGSK3β failed in re-establishing cell polarity. Interestingly, a rescue effect was observed when wt Xdsh and the mutant were coexpressed. This indicates that a balanced level of Wnt/PCP signaling activity is required because reduced or increased activity led to the same defect. A similar observation was made by Tada and Smith7 who blocked Wnt/PCP signaling and convergent extension movements by expressing dn-Xwnt-11. Rescue was only achieved by a moderate concentration of Xwnt-11. The idea of a balanced Wnt-11 signaling activity explains previous findings that overexpression of Xwnt-11 blocks convergent extension. 4
In zebrafish Wnt-11 is encoded by silberblick (sbl). Cell tracking in the silberblick mutant revealed that convergent extension movement is affected. 9 This phenotype is rescued by the dsh mutant (dsh-ΔN) which is not able to mediate Wnt/β-catenin signaling but which still functions in the Wnt/PCP pathway. Transplantation of cells between wt and slb-/- embryos additionally revealed that the required Wnt-11 signal acts in a cell non-autonomous manner. The glypican knypek potentiates the Wnt-11 effect on convergent extension movements,10 most likely by enhancing the ligand receptor interaction. BMP, on the other hand, restricts convergent extension movements by downregulating Wnt-11 and Wnt-5a.11
Posttranslational modifications modulating cell-adhesion or cytoskeleton rearrangements but also JNK dependent gene regulation are discussed as downstream effects of Wnt/PCP signaling (see chapter 6 this issue, see also Ref. 12). The Xwnt-11-dependent cell polarity formation in the vegetal alignment zone6 and also the rescue effects by dominant negative cdc42 in case of Xwnt-11 or XFz-7 overexpression5 argues for a short-term posttranslational regulation. This does not rule out that long-term effects drive convergent extension at the neurula stage. Strabismus (stbm), an interacting partner of dsh in Wnt/PCP signaling, mediates c-Jun and AP-1 dependent transcription of neural marker genes. Expression of a wt-stbm or a dn-stbm inhibited elongation of activin-treated animal caps.8 Since primary stbm expression starts in early neurula and defects of morphogenetic movements in gain or loss of function experiments are deduced from shortened body axis and reduced inter-somite spacing, it seems most likely that long-term effects of Wnt/PCP signaling were monitored here.
In most reports on Xenopus gastrulation the effects of Wnt signaling on convergent extension movements were measured in open-face explants after several hours at the end of the elongation process. In these reports, neither distinction between different types of cell polarity formation (bipolar/mesoderm vs. monopolar/neural-notoplate) was made nor contribution of different tissue layers considered (Fig. 2). The analysis of convergent extension movement in activin-treated animal caps4,5,8 is also handicapped, as this assay poorly reflects the tissue architecture and the combination of the endogenous signaling cascades in the dorsal marginal zone. Depending on the experimental conditions, Wnt signaling cannot be allocated to specific cell behaviours or phases within the time course of convergent extension movements summarised in Figure 2. There are two exceptions: Wallingford et al.6 showed that Wnt/PCP signaling induces the formation of the bipolar cell shape in the deep cells of the dorsal marginal zone when the vegetal alignment zone (VAZ) is formed (Fig. 2). Moreover, Wallingford and Harland13 used targeted expression of Xdsh mutants and Keller sandwich explants to demonstrate that the Wnt/PCP cascade also controls the extension of the neural plate. However, it remains to be clarified whether Wnt/PCP induces monopolar polarity in lateral neural plate cells. In the future, more effort should be made to distinguish between these short- and long-term effects by analysing cell behaviour at different time points and in different tissue layers of explants.
Canonical Wnt/β-Catenin Signaling is Required for Proper Convergent Extension
Overexpression of components of the canonical signaling pathway in Xenopus never led to disturbed gastrulation movement or inhibition of elongation of the embryo. However, blocking the Wnt/β-catenin pathway by overexpression of either secreted forms of Xfz-814, naturally occuring Wnt antagonists15,16 or dominant negative forms of the transcription factor LEF-116 resulted in inhibition of convergent extension movements. Most strikingly, a branching of the canonical Wnt signaling cascade downstream of β-catenin was observed in Xenopus. LEF-1 or the target gene Xnr3 restored convergent extension movements in embryos with blocked canonical Wnt pathway while TCF-3 or the target gene siamois did not. These findings implicate that gene expression, at least Xnr3 expression, is necessary.16
Wnt/β-catenin sigaling also regulates cell movements in zebrafish gastrulation.17 Interestingly, accumulation of β-catenin leads to tyrosine phosphorylation and nuclear localization of Stat3. This activation of Stat3 is TCF-3 dependent, but does not involve the induction of Dharma/Bozozok, Nodal or Wnt-11, the target genes of maternal canonical wnt signaling in zebrafish. Following the migration behavior of prechordal and lateral mesodermal cells with defect Stat3 function in wt embryos, or of wt mesodermal cells in Stat3 deficient host embryos, Yamahita et al.17 demonstrated that Stat3 regulates migration of the prechordal mesoderm cell autonomously while it affects convergent extension movements of the lateral mesoderm in cell non-autonomous manner.
Canoncial wnt signaling seems to affect cell behavior in Xenopus and zebrafish very differently. A cell autonomous influence of Wnt/β-catenin on active migration of the anterior mesoendoderm in Xenopus has not been shown yet. Instead, FGF and activin promote this substrate dependent cell migration.18 A cell non-autonomous Wnt/β-catenin influence on convergent extension movements could be assumed as the required target gene Xnr3, a TGFß family member, is a secreted molecule. In zebrafish, however, the Xnr3 homolog Nodal is not necessary for cell movement. The discrepancies between both organisms in regulation of cell motility might reflect that the corresponding target genes are still unknown and/or that different tissues are compared, e.g., the lateral mesoderm in zebrafish with the axial and paraxial mesoderm or the neural plate in Xenopus.
Wnt/Ca2+-Signaling Blocks Convergent Extension Movement
Overexpression of Xwnt-5a was found to block convergent extension movements in Xenopus. 19 PKC and a constitutively active form of CamKII mimick the Xwnt-5a phenotype confirming the idea of a separate Wnt/Ca2+ pathway.16,20 PKC and CamKII antagonize the canonical Wnt pathway at different levels. PKC blocks the pathway upstream of β-catenin, whereas CamKII blocks it downstream of β-catenin.16 Since CamKII is more active at the ventral side in the Xenopus embryo,20 convergent extension movements will be suppressed in the ventral compartment. Activation of CamKII was also observed by overexpression of Xwnt-11 raising the question whether the Wnt/Ca2+ and the Wnt/PCP signaling cascades are separate pathways. In this context it is interesting to note that strabismus, a component of the PCP pathway, blocks Wnt/β-catenin dependent gene expression.8 The Rho GTPase Cdc42 acts downstream of Xwnt-5a and PKC-α, because the inhibition of convergent extension movements by overexpression of Xwnt-5a or PKC-α was rescued by co-expression of dnXcdc42.21 Dn Xcdc42 was also able to rescue XFz-7 or Xwnt-11 overexpression, both molecules were assigned to the Wnt/PCP-signaling.5 This implicates that cdc42 might function in both pathways or a separation between the Wnt/Ca2+ and the Wnt/PCP pathway appears to be artificial.
Intracellular calcium waves have been shown to occur during gastrulation in zebrafish22,23 and Xenopus.24 Blocking the release of calcium from intracellular stores resulted in inhibition of convergent extension movements in Xenopus open-face Keller explants. The mechanism of calcium wave initiation and propagation, however, remained unclear. A role of Wnt signaling was proven by expression of an N-terminal fragment of Frizzled-8 (NXFz-8) and yielded little influence, because only the frequency of the waves were found slightly reduced.24 Further studies by modulating Wnt/Ca2+-signaling components will answer this question.
Formation of Brachet's Cleft Depends on Wnt Signaling
In Xenopus gastrulation, the anterior involuting mesoderm, also termed head mesoderm, exerts a separate type of migration behaviour. These cells migrate as cohort on the blastocoel roof and use the extracellular matrix, predominantly the fibronectin fibrils, for orientation towards the animal pole.2 During the involution process they alter their surface properties and lose the ability to integrate into the blastocoel tissue after they have moved inside. This results in the formation of the Brachet's cleft which separates the head mesoderm from the blastocoel roof. Downregulation of XFz-7 by anti-sense morpholino injection resulted in loss of Brachet's cleft formation and abolished the separation behaviour of the head mesoderm cells while convergent extension movements were not blocked.25 The latter result is unexpected as overexpression of full length or an extracellular fragment of XFz-7 inhibited elongation of activin-treated animal caps.5 The disturbed separation behaviour upon XFz-7 downregulation could neither be restored by activation of the canonical pathway nor of the PCP signaling pathway which led Winklbauer et al.25 to speculate about a further branching of Wnt signaling pathways. However, the separation behavior was pertussis toxin sensitive and both, disturbance by the toxin or by XFz-7-receptor decrease was rescued by PKC-α expression. This makes a contribution of the Wnt/Ca2+-pathway most likely, particularly, because is has been shown that XFz-7 can signal in the canonical but also in the noncanonical, PKC-α dependent manner.
Wnt Signals Controlling Migration of Neuroblasts and Neural Crest Cells
Wnt signals are known to play a role in the specification and patterning of the nervous system. In C. elegans, Wnt signals play a crucial role in differentiation and migration of neuroblasts. During the first larval stage, the P11/P12 pair of ventral epidermal blast cells migrates to align along the antero-posterior axis. This rotation is biased for the P1/P2 and the P11/P12 pairs. In the latter case, 85% of the right cells adopt the fate of the posterior P12 cell. Although lin-44/Wnt signaling does not change this ratio, disturbed Wnt signaling results in a loss of positonal information. In these mutants, both cells are driven into the P11 lineage26,27 and lack P12.a-derived neurons and P12.p descendants.
Work by Maloof et al.28 shows that Wnt signaling determines cell fate of Q-cell descendants. The QL cell and its descendants migrate posteriorly while the QR cell migrates anteriorly. These opposite migrations are due to canonical Wnt signals. The egl-20/Wnt signaling pathway involves bar-1, a β-catenin homologue29 and POP-1/TCF.30 In the QL cell egl20/Wnt signaling is inhibited by pry-1, leading to posterior migration. In the QR cell, Wnt signaling induces the expression of the Hox gene mab-5, which has been shown to be sufficient to reverse the direction of cell migration. In the absence of pry-1, both Q-descendants behave like the wild-type QR cell.28
In vertebrates, Wnt signals contribute to the patterning of the brain and the peripheral nervous system. Wnt-1 and Wnt-3A are expressed along the dorsal midline in the mouse.31,32 In this region neural crest cells derive from neural precursors and start to emigrate from the neural tube towards their destined position in the embryo (see Fig. 3). Neural crest cells contribute to a variety of structures, e.g., they form part of the peripheral nervous system, ganglia and Schwann cells. Another subset of neural crest cells differentiates into melanocytes and migrates all over the body to form a specific pigmentation pattern.
Wnt signals have been shown to be involved in neural crest specification. Wnt-1 and Wnt-3a promote melanocyte formation at the expense of neuronal cell fates in the zebrafish.33 Later studies indicate a role of canonical Wnt signaling not only in the specification but also in migration of melanocytes. Wnt expression is maintained from the onset of neural crest emigration until the completion of melanocyte migration in the avian embryo.34 Thus, Wnts are expressed in the right place and at the right time to influence neural crest cell specification and migration. In vitro experiments showing a correlation between Wnt signaling and neural crest migration35 support this assumption.
The in vivo situation seems to be more complex. Double knockout mice, which lack both Wnt-1 and Wnt-3A, show significant reduction or even absence of neural crest cells. This seems to be due to defects in the induction of neural crest cell fates, as marker gene expression is also altered. A decrease in CRABP-1 as well as AP-2 positive migrating cells was observed, while AP-2 expression persisted in the neural tube. Additionally, a dramatic reduction in Pax-3 expression was noted36. Taking into account that Splotch-mice which lack functional Pax-3 show severe defects in neural crest formation probably due to disturbed cell-cell interactions37, these findings point to an indirect influence of Wnt signals in neural crest migration.
The importance of proper cell-cell interactions is shown by the effect of overexpressing cadherin-11 or deletion mutants of cadherin-11 in Xenopus. Overexpression of cadherin-11 constructs containing the extracellular domain, thus enhancing cell adhesion, completely suppresses cranial neural crest cell migration and promotes a neuronal cell fate. Disturbance of cell adhesion by expression of a extracellular deleted mutant leads to premature migration and suppression of twist-expression. The latter is due to a depletion of the endogenous ß-catenin pool and is rescued by co-expression of β-catenin. This strongly indicates the importance of canonical Wnt signaling for the maintenance of cranial neural crest cell fate during migration. 38 Recent studies in chicken embryos support a differential mechanism of specification and migration for neural crest cell subtypes. For melanocytes few TRP-2 (tyrosinase-related protein-2)39 positive precursor cells form, but are unable to emigrate from the neural tube.36 Emigration itself follows a certain time course depending on the neural crest cell subtype. Early neural crest cells which differentiate into neuronal and glial precursors are formed under the control of BMP-4 although Wnts are expressed in the neural tube from the very beginning of neural crest differentiation. These neural and glial precursors secrete the Wnt antagonist cFrzB-1. In later stages of neural crest formation, the expression of BMP-4 and cFrzB-1 ceases with the onset of melanocyte migration. The persisting Wnt-signal drives the later neural crest cells into the melanocyte lineage and also seems to be involved in the emigration of melanocyte precursors from the dorsal midline. Furthermore, Wnt-7A directs melanocyte localisation to the dorsal side of developing limbs (Fig. 3). Wnt-7A is expressed on the dorsal side of growing limb buds, while its expression on the ventral side is repressed by engrailed-1. Ectopic expression of Wnt-7A on the ventral side induces dorsal patterning including pigmentation, thus implicating that Wnt-7A signals are involved in the direction of migrating melanocytes to the dorsal side of extremities.34
Wnt Signals Influence the Migrational Behavior of Myocytes
Wnt-1 and Wnt-3 in the chicken40,41 as well as Wg in Drosophila42,43 have been shown to induce myogenesis. Besides this determining role, Wnts play an additional role in the control of myocyte motility.
In the mouse Wnt-5A and Wnt-3A induce expression of N-cadherin in cardiac myocytes and of E- and M-cadherin in fibroblasts. The enhanced cadherin-mediated cell adhesion seems to be a prerequisite for the formation of myocyte aggregates in the presence of fibroblasts. Therefore, Wnt-5A or Wnt-3A signals decrease the mobility of cardiac myocytes in the mouse and favor their aggregation.44
In Drosophila DWnt-2 was shown to control myocyte migration in the male genital tract. DWnt-2 expression patterns are sexually dimorphic. Expression in the genital disc and gonadal mesodermal cells is observed only in males. During gonad development, the gonad and the genital disc contact and fuse with each other. In the male, the genital disc forms the external organs of the genital tract and a pigmented sheath that surrounds the testes and the seminal vesicle. In females the genital sheath is not pigmented. The myocytes and the pigment cell precursors in males are formed in the genital disc, emigrate from the disc as it is contacted by the gonad and subsequently migrate all over the gonad and finally envelop it (Fig. 4).
In DWnt-2 null mutants, the formation of the muscle sheath enclosing the reproductive tract is selectively disturbed in males. DWnt-2 induces the differentiation of the male specific pigment cells and the migration of myocytes from the genital disc to and over the testis. Although the molecular mode of this effect has not yet been clarified, it is presumed that DWnt-2 might be involved in the induction of myocyte migration from the genital disc, their attachment to the testis or both events.45 An even more general role of DWnt-2 in the control of myocyte migration is indicated by a recent study. It has been shown that in DWnt-2 mutants the direct flight muscles are either missing or fail to attach to the correct sites. DWnt-2, which is expressed in the adjacent epithelial cells, might act as a directional signal for myocyte migration. 46
Canonical Wnt Signaling Controls Tracheal Cell Migration
The Drosophila tracheal system originates from ten pairs of ectodermal placodes. The tracheal cells first invaginate from the placodes to form tracheal sacs. The five primary tracheal branches (dorsal branch, anterior and posterior dorsal trunk branch, visceral branch, lateral trunk branch and ganglionic branch) grow out from these sacs. Further branching leads to the formation of a complex network. The invagination of the cells from placodes and the formation of the five primary branches are influenced by different signals: FGF, decapentaplegic (Dpp, a TGFβ homolog), EGFR signaling, activation of the MAPK pathway and Wnt/Wg. While FGF signaling is required for the migration of all tracheal cells from the cellular sacs, Dpp and Wnt/Wg each regulate the migration of cells to specific primary branches. Failure of Dpp signaling causes the loss of the dorsal branch, lateral trunk branch and ganglionic branch.47,48 Wnt/Wg signaling directs the cells forming the anterior and posterior dorsal trunk branches.49,50 In Drosophila mutants with defects in Wnt/Wg or downstream components of the canonical Wnt signaling pathway, the cells of the dorsal trunk branches fail to leave the transverse connective region. As this phenotype is stronger if downstream components like β-catenin/armadillo or TCF are affected, Wg might not be the only Wnt molecule involved in the regulation of tracheal cell migration.50 Additionally, it has recently been shown that ribbon, a BTB/POZ protein, acts in parallel to or downstream of FGF and Wnt/Wg signaling to promote directed cell migration. If one assumes a crosstalk between ribbon and the Wnt/Wg pathway downstream of Wg itself, mutations of downstream components should show stronger phenotypes because of the failure to respond to ribbon.51
In summary, the state of the art on Wnts function in cell migration yields more open questions than answers. The reports provide evidence that different Wnt signaling pathways control cell motility in various morphogenetic movements. While Wnt/PCP seems to act by confering polarity to cells, the roles of the Wnt/β-catenin or Wnt/Ca2+ pathways on cellular level are completely unknown. In addition, the studies reveal that different pathways can influence each other, and further branching points in the pathways seem to exist. The current aim is to decipher the network of downstream signal transducers and effectors, predominantly in the Wnt/PCP and Wnt/Ca2+ cascade, and to link them with cellular events driving motility. The future challenge will be to depict the spatiotemporal activity of regulators in mass tissue movements that regulates adhesive strength, cytoskeleton re-arrangements, orientation and polarity of cells in different tissue compartments.
We thank Dr. K. Astrahantseff for helpful discussions and critical reading of the manuscript.
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Alexandra Schambony and Doris Wedlich.
Landes Bioscience, Austin (TX)
Schambony A, Wedlich D. Wnt Signaling and Cell Migration. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.