Organizing moving groups during morphogenesisVirginie Lecaudey and Darren Gilmour

The directed migration of cells drives the formation of many

complex organ systems. Although in this morphogenetic

context cells display a strong preference for migrating in

organized, cohesive groups, little is known about the

mechanisms that coordinate their movements. Recent studies

on several model systems have begun to dissect the

organization of these migrating tissues in vivo and have shown

that cell guidance is mediated by a combination of chemical

and mechanical cues.

Addresses

European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117

Heidelberg, Germany

Corresponding author: Gilmour, Darren (gilmour@embl.de)

Current Opinion in Cell Biology 2006, 18:102–107

This review comes from a themed issue on

Cell structure and dynamics

Edited by J Victor Small and Michael Glotzer

Available online 13th December 2005

0955-0674/$ – see front matter

# 2005 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.ceb.2005.12.001

IntroductionCell migration is essential to many physiological and

disease processes such as embryonic morphogenesis,

wound healing and cancer metastasis. Studies on single

motile cells in culture have lead to a well-established

model whereby cells move via the extension and adhesion

of a leading edge pointed in the direction of migration and

the retraction and loss of adhesion of the trailing edge at

the rear. Here, the forces required for the translocation of

the cell body are generated at the points of contact with

the flat substrate provided by the Petri dish. While these

studies have been crucial in understanding the mechanics

of cell motility, it is clear that this controlled experimental

environment is very different from what cells experience

in the three-dimensional context of living tissues. How-

ever, thanks to improvements inmicroscopy technology it

is now possible to observe cells migrating in their natural

habitats, such as the intact developing embryo. What has

become clear from imaging studies is that during mor-

phogenesis cells do not usually travel alone but rather

prefer to undertake journeys together, often moving in

very large numbers. In some cases cells move as dense

streams of freely migrating chemotactic individuals that

coalesce at particular locations, with each cell apparently

Current Opinion in Cell Biology 2006, 18:102–107

being guided directly by extrinsic cues [1��]. However,

during the morphogenesis of many organ systems it is

more common to find cells migrating in some form of

adherent group or as tissues. These ‘tissue migrations’ are

the focus of this review.

Migrating tissues come in many shapes and sizes and

show varying degrees of cohesion and organization (for

more details see [2]) (Figure 1). These range from rather

loose networks, such as chains of neuronal progenitors in

the CNS [3,4] and migrating neural crest cells [5�], totightly adherent sheets of epithelial cells, where a large

number of cells move as a single coherent unit and

maintain constant positions throughout [6]. Elsewhere,

they can be found as clusters of motile cells, as exempli-

fied byDrosophila border cells (BCs) [7,8] or the migrating

primordium of the lateral line (LLP) in amphibia and fish

[9,10]. Migrating tissues are often employed in sculpting

complex three-dimensional forms, including the intricate

tubular networks present in the vasculature and the

respiratory system. While their forms and functions are

diverse, it is clear in all cases that the migratory behaviour

of cells within these various tissues must be coordinated

to ensure proper movement of the entire group. The aim

of this review is to integrate some recent results from

several experimental models that shed light on the

mechanisms ensuring the concerted movement of tissues

during morphogenesis. Because of space limitations, we

will not discuss convergent-extension movements during

gastrulation, a very important example of collective cell

behaviour that has been covered by several excellent

recent reviews [11,12].

Getting organized for the journeyWhat guides cell groups on their journey? Genetic studies

in a wide range of model systems have shown that tissue

migration is regulated by the very same extrinsic chemical

cues that guide single cells. Examples include members

of the epidermal growth factor and fibroblast growth

factor families, which are detected through receptor tyr-

osine kinases present in the plasma membrane. As these

are known to guide single cells via a chemotactic mechan-

ism, it is likely that graded distributions of these factors

also determine the directionality of tissue migration in

many cases [1��,13]. An important issue regarding cells

moving as a cohesive tissue is the extent to which external

gradients penetrate multicellular cohorts to control migra-

tion behaviour within. It is becoming clear that extrinsic

cues drive the movement of tissues not by acting directly

on all members of the group but rather by instructing

smaller numbers of peripheral leader cells that in turn are

responsible for the guidance of naıve followers. This is

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Organizing moving groups during morphogenesis Lecaudey and Gilmour 103

Figure 1

Cells move in groups of varying shape and size in vivo. (a) The concerted movement of epithelial sheets is a very prevalent feature of morphogenesis,

as demonstrated here during dorsal closure in the Drosophila embryo. (b) The coordinated migration of groups of epithelial cells also drives the

formation of branched tubular networks, such as the Drosophila tracheal system. (c) Chain migration of neuronal precursors in the subventricular

zone of the adult rodent brain. (d,e) Drosophila border cells and the zebrafish lateral line primordium as two examples of cells that migrate in

clusters or cohorts. (Reproduced with permission of (a) Ferenc Jankovics and Damian Brunner; (b) Stefan Luschnig; (c) Arturo Alvarez-Buylla, in [4];

(d) Pernille Rorth, in [18]).

suggested by the fact that in many contexts only a subset

of cells within a tissue display morphological features,

such as filopodia and pseudopodia, characteristic of migra-

tory cells [14]. Further support comes from several studies

where guidance receptor activation is assayed directly

using antibodies that bind specifically to active forms of

receptors or downstream signalling components, allowing

the identification of responsive cells. This approach was

first used with anti-phospho-MAPK (Erk) antibodies to

show that FGF signalling becomes restricted to the tips of

Drosophila tracheal branches soon after they begin to

extend [15]. More recently, anti-phosphotyrosine antibo-

dies have been used as a read-out of guidance receptor

activation to show that during normal migration only a

subset of BCs responds to the cue secreted by the oocyte

[16]. Similarly, during eyelid closure in mouse embryos,

the EGF-like growth factor HB-EGF binds to and acti-

vates the EGF receptor and the downstream ERK signal-

ling cascade only at the leading edge of the migrating

epithelial sheet [17]. The most direct experimental

demonstration that not all cells within migrating tissues

need to respond to cues in vivo comes from genetic mosaic

studies that juxtapose wild-type and migration-defective

mutant neighbours. This approach has been particularly

informative in the case of Drosophila BC clusters, where

wild type cells have been mixed with several different

immotile mutants including slbo, shg (E-cad) and sqh(myosin II). Here the wild-type cells can rescue the

migration of immobile mutant clusters with an efficiency

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depending on their proportion [18–20]. These combined

findings demonstrate clearly that guidance within tissues

can be non-cell-autonomous, and that groups are com-

posed of cells that respond directly to extrinsic cues and

cells that do not.

Coordinating individual movements withinmoving groupsChemotaxis: tips from a slimy collaborator

How do these leading cells transmit this extrinsic direc-

tional information to the remainder of the group? One

paradigm for how cells within motile groups can organize

each other’s behaviour comes from Dictyostelium slugs,

which are comprised of many thousands of migrating cells

that move collectively [21]. Here, a specialized set of cells

at the tip of the slug, known as the prestalk cells, form an

internal source of the diffusible chemoattractant cAMP

that drives periodic waves of migration throughout the

entire mass. Responding posterior cells are dependent on

this internally generated gradient for their motility; if the

tip region is cut off, it continues to migrate while the

remainder of the slug is rendered immobile [22]. While

tissues moving through embryos are guided by extrinsic

cues, it is possible that leading cells adopt a similar

strategy to organize the migratory behaviour of neigh-

bours through a relay of guidance molecules. It will be

interesting to determine whether the expression of che-

moattractants within moving cohorts provides a mechan-

ism for coordinating their behaviour in vivo.

Current Opinion in Cell Biology 2006, 18:102–107

104 Cell structure and dynamics

Mechanotaxis: can you feel the force?

In many situations it is more likely that leading cells

organize their neighbours by translating extrinsic chemi-

cal guidance cues into directional mechanical force. The

force in question originates at least in part when leading

cells retract their trailing edges, an event that in single

cells is known to be dependent on the activity of myosin

II [23]. Interestingly, Dictyostelium mutants lacking myo-

sin II are able to migrate as single cells but cannot make

slugs, suggesting that force generated through the actin–

myosin network plays an important role in allowingmulti-

cellular movements [24,25]. Likewise, in BC clusters

where the activity of myosin II is reduced, the leading

cell continues to project long cellular extensions (LCEs)

in the direction of migration, suggesting it can respond to

guidance cues, but is unable to translocate its cell body or

the remainder of the cluster, supporting the idea that

contraction of the leading cells generates the force that

initiates group migration [18,26].

An open question in the field is how followers detect the

mechanical tension generated by leading cells in response

to chemical cues. Focal adhesion complexes that form

between cells and the substratum have been shown to

mediate the conversion of external mechanical forces into

biochemical intracellular responses [27]. In the case of

cohesive groups, it is likely that mechanical force is

transduced at points of cell–cell contact, with adherens

junctions (AJs) being the best candidates, a suggestion

supported by recent work on cultured endothelial cells

(ECs). As ECs line the luminal surface of blood vessels

they are constantly exposed to pressure from the passing

flow, termed shear stress, and it is known that hemostatic

pressure influences many aspects of EC behaviour,

including the directionality of their migration [28]. In a

recent paper, Tzima and colleagues have described a

mechanosensory complex present at AJs; this complex

comprises two cell adhesion molecules (PECAM-1 and

vascular endothelial cell cadherin) and a receptor tyrosine

kinase (VEGFR2) and is required for the coordinated

alignment of ECs in response to shear pressure [29��].Cadherins have also previously been shown to mediate

mechanical signalling at cell–cell junctions in fibroblasts

through the activation of stretch-sensitive calcium chan-

nels leading to an increase in actin polymerization [30]

(Figure 2). Calcium signalling has also been shown

recently to modulate cell speed in response to shear stress

in Dictyostelium [31] and to be involved in detachment of

the rear of migrating fish keratocytes [32]. This is parti-

cularly intriguing as it has been proposed that the pro-

pagation of calciumwaves across fields of cells may be one

mechanism for coordinating their movements [33].

How do cells respond when placed under mechanical

stress by their more informed neighbours? Several recent

studies indicate that, rather than simply coming along for

the ride, cells within tissues react in a way that enhances

Current Opinion in Cell Biology 2006, 18:102–107

the mobility of the group. By scratching ‘wounds’ in

cultured MDCK epithelial monolayers, Farooqui and

Fenteany have demonstrated that cells several rows

behind the wound margin extend ‘cryptic’ lamellipodia

basally while maintaining continuous cell–cell contacts

apically, suggesting that these cells are actively involved

in driving collective migration [34�]. Interfering with

either intracellular calcium or gap junctions had no effect

on this behaviour, leading to the proposal that it may be

stimulated through a direction-sensingmechanotransduc-

tion system present at apically located junctions. Using

the same culture system it has recently been shown that

scratching induces two waves of ERK1/2-type MAP

kinase activation propagating from the wound edge to

submarginal cells [35]. The second wave is tightly corre-

lated with the motility of the cells; it is no longer present

as the wound is closing and inhibition of ERK1/2 activa-

tion results in a clear reduction in the rate of migration.

Although the mechanism of propagation is not known, it

is suggested once again that mechanical tension spreading

from the leading edge induces a response in neighbouring

cells — ERK activation in this case — that in turn is

necessary for sheet migration (Figure 2).

Recent papers describe an elegant regulatory mechanism

whereby migration-induced tension influences the status

of the actin cytoskeleton in responding cells via the

activity of the serum response factor (SRF). SRF is a

transcription factor that controls the expression of several

growth-factor-induced genes and is required for cell

motility in several contexts [36–38]. A large body of work,

mainly from Richard Treisman’s laboratory, has shown

that SRF activity is potentiated by situations that stimu-

late actin polymerization, such as Rho GTPase signalling

[39]. The mechanism underlying this regulation

remained obscure until their recent demonstration that

the SRF co-activator MAL moves from the cytoplasm to

the nucleus upon Rho-actin signalling. Once there, it

stimulates the expression of SRF target genes, including

regulators of actin itself. Somogyi and Rorth have recently

described the isolation of mutants in the Drosophilahomologue of MAL (MAL-D, also known as DMRTF),

which show a strong BC migration defect that is appar-

ently due to an inability to organize a robust actin cytos-

keleton [40��]. In this multicellular context, the nuclear

localization of MAL-D appears to be dynamically regu-

lated and shows a clear correlation with cell shape; MAL-

D is observed in the nuclei in a subset of cells in stretched

wild-type clusters whereas it remains cytosolic in all cells

in rounded slbo mutant clusters. Ingenious in vivo ‘pull-

ing’ experiments demonstrate that slbomutants can trans-

locate MAL-D to the nucleus when tugged by motile

wild-type cells, confirming that this is indeed a direct

response to stretching. Given that SRF regulates the

transcription of actin regulators, these data suggest a

positive feedback loop where cytoskeletal changes

induced by pulling forces lead to the nuclear translocation

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Organizing moving groups during morphogenesis Lecaudey and Gilmour 105

Figure 2

Model for the coordinated migration of adherent cells in response to guidance cues. (a) Two hypothetical adherent migratory cells, here held

together through cadherin–catenin complexes, in the absence of guidance cues. (b) Upon exposure to a graded distribution of attractant the cell

nearest to the source adopts a ‘leader’ role. It polarizes, projects lamellipodia and filopodia and stretches in the direction of the cue. (c) Rear

retraction of the leading cell exerts mechanical force and can evoke a variety of responses in the ‘following’ cell, such as the entry of calcium via

stretch-induced calcium channels or the activation of ERK 1/2. Tension-induced changes in the cytoskeleton can promote the nuclear translocation

of the SRF cofactor MAL. SRF/MAL then upregulates the expression of actin regulators to strengthen the cytoskeleton and enhance cell

migration.

of MAL-D, which results in the concomitant strengthen-

ing of the cytoskeleton required for cell migration.

Furthermore, an independent study has shown a require-

ment for MAL-D in regulating the migration of both

tracheal and mesodermal cells [41�]. During tracheogen-

esis, loss of MAL-D function causes a truncation of

terminal branches, a phenotype that has been previously

described in Drosophila SRF mutants [37,38], whereas

expression of a hyperactive form of MAL-D that is con-

stitutively nuclear causes their overgrowth. While the

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MAL-D loss-of-function allele has no obvious mesoderm

phenotype, expression of the constitutively nuclear form

appears to enhance the migration of mesodermal cells

such that they end up located more dorsally than normal.

In both cases, forced nuclear localization of MAL-D

apparently leads to increased migratory behaviour, in

accordance with the finding that it strengthens the cytos-

keleton. As both the trachea and mesoderm move as

adherent groups of cells, it will be interesting to know

whether MAL-D activity is modulated by cell–cell

stretching in these and other contexts.

Current Opinion in Cell Biology 2006, 18:102–107

106 Cell structure and dynamics

ConclusionsIt is becoming clear that group migration is regulated by

the combined influence of extrinsic chemical guidance

cues and local mechanical interactions between cells. A

complete understanding of this complex problem will

therefore require a multi-disciplinary approach. Several

recent papers have combined the use of genetics, imaging

and physical ‘tools’ to study the forces involved in

embryonic movements with exciting results. For exam-

ple, atomic force microscopy has been used to measure

the adhesive forces generated by primary zebrafish

embryonic cells plated on cadherin substrates, and these

quantitative findings have been correlated with the cells’

in vivo behaviour [42]. Similarly, a combination of laser

microsurgery and quantitative modelling has been used to

dissect the forces driving morphogenetic movement dur-

ing dorsal closure in Drosophila [43]. On the imaging side,

it will be essential to develop probes that allow the

mechanical activation of biochemical pathways to be

monitored and quantified within living embryos. Once

again, many recent developments show great promise in

this regard, such as FRET probes that can monitor the

dynamics of SRC activation upon mechanical stimulation

[44]. Finally, the identification of biochemical systems

that convert mechanical tension into different types of

migratory behaviour will be a high priority for the future.

AcknowledgementsWe are grateful to Pernille Rorth, Francesca Peri, Petra Haas and StefanEimer for critical reading of the manuscript. We thank Ferenc Jankovics,Damian Brunner, Stefan Luschnig, Arturo Alvarez-Buylla and PernilleRorth for images. V.L. was supported by a fellowship from la Fondationpour la Recherche Medicale.

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Current Opinion in Cell Biology 2006, 18:102–107