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. Author manuscript; available in PMC: 2019 Aug 20.
Published in final edited form as: Dev Cell. 2018 Aug 20;46(4):389–396. doi: 10.1016/j.devcel.2018.08.003

Coming to consensus: A unifying model emerges for convergent extension

Robert J Huebner 1, John B Wallingford 1,*
PMCID: PMC6140352  NIHMSID: NIHMS1502953  PMID: 30130529

ETOC blurb

Huebner and Wallingford present a Perspective to describe the connection between cell intercalation during convergent extension and individual cell migration. They describe the cell biological underpinnings of both processes and their similarities and differences in both processes.

Introduction

Cell motility is a widespread biological property that is best understood in the context of individual cell migration. Indeed, studies of migration in culture have provided tremendous insight into the signals and mechanics involved and have laid the foundation for our understanding of similar migrations by larger cellular collectives. By contrast, our understanding of another flavor of movement, cell intercalation during convergent extension, is only now emerging. Here, we integrate divergent findings related to intercalation in different settings into a unifying model, paying attention to how this model does and does not resemble current models for directed cell migration.

Cell migration versus cell intercalation

The simplest form of cell motility is a single cell crawling on a two dimensional substratum (Fig. 1A) and during this form of migration individual cells respond to diverse biochemical or biomechanical cues by executing behaviors along a front-to-rear polarity that is initiated and maintained by asymmetric localization of signaling molecules, membrane lipids, adhesion molecules, and organelles (Charras and Sahai, 2014; Ridley et al., 2003). Such cellular polarity drives remodeling of the cytoskeleton to produce actin-based protrusions at the leading edge and actomyosin driven contractions at the lagging edge (Huttenlocher and Horwitz, 2011). Finally, contractile actomyosin located behind the leading protrusions engages ECM-bound focal adhesions to produce traction force and motility (Gardel et al., 2010). This type of migration has been studied extensively in vitro, but critically, similar behaviors are observed in migrating stromal fibroblasts, the neural growth cone, and metastatic cancer cells in vivo (Even-Ram and Yamada, 2005)

Figure 1.

Figure 1.

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Cell migration differs from cell intercalation. A. Individual cell migration involves traction against an ECM and actin (red) assembly in the leading and lagging edges. B. In the “crawling” model for cell intercalation, initially set forth in mesenchymal cells, mediolaterallydirected (here, horizontal) protrusions act in a manner analogous to leading edges to drive mediolateral intercalation by cell crawling. C. In the “junction shrinking” model for cell intercalation, initially set forth in epithelial cells, movement is driven by actomyosin-mediated shrinkage of mediolaterally-aligned cell-cell junctions.

By contrast, cell intercalation (Fig. 1B, C) refers to the polarized movement of one cell between neighboring cells, and iterative intercalation events result in tissue remodeling. There are several variants on cell intercalation, including radially-directed intercalations during gastrulation, tube elongation, and cell insertion into epithelia (Neumann et al., 2018; Sedzinski et al., 2016; Szabó et al., 2016). However, by far the most intensely studied are the mediolaterally-directed intercalations that drive convergent extension. Though far less studied than individual migration, convergent extension is an absolutely fundamental process that drives elongation of diverse tissues in animals ranging from nematodes and arthropods to vertebrates (reviewed by (Shindo, 2018; Tada and Heisenberg, 2012; Walck-Shannon and Hardin, 2014; Williams and Solnica-Krezel, 2017)). Moreover, failure of cell intercalation is thought to underlie catastrophic birth defects in humans, including neural tube defects and skeletal dysplasia (Butler and Wallingford, 2017; Wallingford et al., 2013). Despite its importance and its widespread deployment in tissues and animals, a unifying model to describe the cellular and molecular mechanisms driving intercalation is only now emerging. Illuminating the arguments for and opposed to this unified model is a key goal of this perspective.

The second major goal of this perspective is to place our understanding of cell intercalation into the larger context of cell movement and migration. In some ways, intercalation is similar to migration, as both processes share molecular regulators such as the Rho GTPases and both generate force for movement using polarized deployment of actomyosin. On the other hand, intercalation also differs from migration in fundamental ways. First, the majority of cell movement is actually perpendicular to the direction of bulk tissue deformation (Fig. 1B, C), and two axes of polarization appear to guide intercalation, as opposed to a single axis of front-rear polarity. In addition, force for intercalation seems to be exerted primarily on neighboring cells as opposed to the ECM, so the mechanisms of adhesion and force generation appear quite different from those in migrating cells. Historically, two key models have been put forth to explain the cellular mechanism of intercalation (Devenport, 2016; Shindo, 2018), and these mechanisms have been thought to relate to the mesenchymal or epithelial nature of the cells involved. As we will discuss in the following sections, it now seems clear that both mechanisms act in concert in cells of both types.

Intercalation by cell crawling

The first description of cell intercalation likely comes from Walther Vogt, who in 1922 described a “longitudinal staggering of the cell complexes” occurring during amphibian gastrulation (Vogt, 1922). Appropriately, the first detailed cellular model for intercalation arose from work with mesodermal cells during gastrulation in the frog, Xenopus (Keller, 2002; Keller and Tibbetts, 1989; Keller and Hardin, 1987). Given the mesenchymal nature of these cells, the model drew heavily on studies of individual cell migration. In this model (Fig. 1B), cells undergo a progression of behaviors involving alignment in the axis of intercalation and polarized formation of cellular protrusions that resemble lamellipodia. These protrusions make stable contacts with, and exert traction on, neighboring cells, thereby driving intercalation in a manner similar to that in migrating cells (Keller and Tibbetts, 1989; Shih and Keller, 1992a; Wilson and Keller, 1991). It is important to note that intercalation of cells is oriented along the mediolateral (ML) axis, thereby driving the perpendicular elongation of the tissue along the anteroposterior (AP) axis.

Interestingly, mesenchymal cells differ from epithelia, displaying undefined cell-cell junctions (e.g. no adherent or tight junctions) and reduced adhesion, as well as a lack of apparent apico-basal polarity (Hay, 2005). Mesenchymal cells can nonetheless form fairly adherent sheets capable of both collective migration (Collazo et al., 1993) and cell intercalation (Shih and Keller, 1992b). This point will become relevant as we seek below to unify this cell crawling mechanism with an alternative mechanism put forth from studies in epithelial cells.

Intercalation by junction shrinking

Shortly after the description of intercalation behaviors in Xenopus, cell intercalation during axis elongation was described in the epithelial cells of the germ band in the fruit fly Drosophila (Irvine and Wieschaus, 1994). In this case, highly adherent epithelial cells are bounded by well-defined, apically positioned cell-cell adhesions; so polarized cell movement requires the polarized remodeling of these junctions. Subsequent studies revealed that this remodeling is achieved by the specific contraction of cell-cell junctions aligned along the dorsoventral (Ffrench-Constant et al.) axis (termed v-junctions) followed by perpendicular extension of new cell-cell junctions aligned along the AP-axis (t-junctions)(Bertet et al., 2004; Blankenship et al., 2006). In the germ band, such junction exchanges bring cells together in the DV axis while pushing cells apart in the AP axis, and tissue elongation is achieved through numerous iterations of these exchanges involving many cells.

Junction exchanges have been shown to take several forms, depending on the number of cells involved. The simplest form, termed t1-transitions, involves four cells and the exchange of one v-junction for one t-junction (Bertet et al., 2004). More complex junction exchanges also occur, in which multiple v-junctions shrink concurrently, forming an intermediate state where cells meet at a single multicellular junction, termed a rosette, which then resolves perpendicularly by forming new t-junctions (Blankenship et al., 2006). It is also worth mentioning that the biomechanics driving intercalations in Drosophila have now been extensively studied (Guirao and Bellaïche, 2017) and that this exchange mechanism is evolutionarily conserved, having now been observed by time-lapse imaging in Xenopus kidney tubules (Lienkamp et al., 2012), the mouse primitive endoderm (Trichas et al., 2012), and the C. elegans nerve cord (Shah et al., 2017).

A unified model for cell intercalation

Though most discussions have highlighted differences between the two cell intercalation models (Devenport, 2016; Shindo, 2018), it is becoming increasingly apparent that these mechanisms have more in common than previously recognized. The initial breakthrough can be traced to an under-appreciated study that described mediolaterally-oriented protrusions in convergent extension of epithelial cells in the C. elegans dorsal hypodermis (Williams-Masson et al., 1998), suggesting that cell crawling might contribute to intercalation in epithelial cells. Some 15 years later, the converse possibility emerged when junction shrinking was observed during intercalation of mesenchymal cells in Xenopus (Shindo and Wallingford, 2014). This study investigated cell-cell junctions in the Xenopus dorsal marginal zone, the same tissue where cell crawling was proposed, but looked 4–5 microns into the cell beyond the substratum and protrusions. They revealed that polarized shrinkage of v-junctions contributed to tissue elongation in the mesoderm.

Together, these results suggested that the cell crawling and junction shrinking mechanisms may actually act in concert, and definitive evidence for such a model emerged from a sophisticated study using time-lapse imaging in mouse embryos cultured ex utero (Williams et al., 2014). Movies from 8-day-old mouse embryos revealed that neural epithelial cells underwent cell intercalation and displayed both T1 transitions and rosettes similar to those observed in Drosophila epithelial cells, as well as mediolaterally-oriented cellular protrusions reminiscent of those in mesenchymal cells of the Xenopus mesoderm. Strikingly, these behaviors were spatially distinct, with cellular protrusions forming at the basal surface of cells, and junction-shrinkage being evident apically (Fig. 2) (Williams et al., 2014).

Figure 2.

Figure 2.

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A unified model for cell intercalation during convergent extension. Panels A-C represent successive stages of intercalation, in which apically-localized junction shrinking and basolateral cell crawling act in concert. The model is based on work from Williams et al., 2014 and Sun et al., 2017. Herein, we suggest that mesenchymal cells also exploit a hybrid model, though how the cell crawling and junction shrinking are spatially organized remains poorly defined.

Most recently, a second study has confirmed this hybrid cell crawling and junctionshrinking model. In this paper, basally-directed, DV-oriented protrusions were described during cell intercalation in the Drosophila germ band epithelium (Sun et al., 2017), where the junction shrinking model had first been delineated. These protrusions clearly occurred prior to cell-cell junction exchange and were shown to resemble the leading edge of migrating cells, displaying characteristic enrichment of actin, lipids, and activated Rac (Sun et al., 2017). Most importantly, the two behaviors were independently regulated, as protrusions were dependent on Rac and Src42A activity and junction shrinking required Myosin 2 contractility (Sun et al., 2017). Also, specific disruption of either protrusions or junction shrinking was sufficient to impact cell intercalation (Sun et al., 2017). Thus, data from across the animal tree of life point to a common mechanism for cell intercalation in which cell crawling and junction shrinkage work in concert to drive cell movement. While this model may be satisfying and parsimonious, key questions remain relating to the molecular mechanisms driving each cell behavior as well as to the mechanisms integrating the two.

Planar cell polarity signaling and cell intercalation

One core molecular system controlling polarized behaviors during cell intercalation is the Planar Cell Polarity (PCP) signaling system, a conserved protein interaction network that establishes polarity in diverse tissues (Butler and Wallingford, 2017). Curiously, while PCP signaling was first discovered in Drosophila (Butler and Wallingford, 2017), this system seems largely dispensable for cell intercalation in that animal (Zallen and Wieschaus, 2004). Rather, the role for PCP signaling in cell intercalation was described first in fish and amphibians (Heisenberg et al., 2000; Tada and Smith, 2000; Wallingford et al., 2000), and has now been found to act in both mesenchymal and epithelia tissues in all vertebrates examined (Greene et al., 1998; Nishimura et al., 2012; Ybot-Gonzalez et al., 2007a) as well as non-vertebrate chordates (Keys et al., 2002) and the C. elegans nerve cord (Shah et al., 2017).

PCP signaling was first linked to actomyosin contractility through the Rho/Rho kinase (ROCK) pathway in Drosophila wing hairs (Strutt et al., 1997; Winter et al., 2001), and PCP proteins act via similar mechanisms during cell intercalation (Habas et al., 2001; Marlow et al., 2002; Tahinci and Symes, 2003; Ybot-Gonzalez et al., 2007a). PCP in vertebrates has also been linked to Src and Rac (Andreeva et al., 2014; Habas et al., 2003), which is of interest because these effectors also play well-known roles in individual cell migration. Interestingly, manipulations of PCP disrupt both junction shrinking and mediolaterally-biased protrusions (Lienkamp et al., 2012; Shindo and Wallingford, 2014; Wallingford et al., 2000; Williams et al., 2014; Yen et al., 2009), but exactly how the PCP proteins impact the actomyosin machinery at these locations remains unclear.

During junction shrinking, loss of PCP disrupts planar polarization of actomyosin, which is normally enriched at v-junction cell faces (Lienkamp et al., 2012; Nishimura et al., 2012; Shindo and Wallingford, 2014; Williams et al., 2014). This makes sense because polarized distribution of core PCP proteins is fundamental to PCP signaling (Strutt, 2002), and core PCP proteins localize to anterior and posterior cell faces (i.e. mediolaterally aligned cell-cell junctions) (Butler and Wallingford, 2018; Ciruna et al., 2006; Ossipova et al., 2015; Yin et al., 2008). It is tempting to speculate that PCP proteins act directly via RhoA and Rho Kinase at these locations to activate myosin, and a recent report indicates that PCP proteins also display oscillatory enrichment together with actomyosin at V-junctions (Butler and Wallingford, 2018).

A more nettlesome question relates to the role of PCP proteins in protrusive activity. Irrespective of their location at AP faces, PCP proteins act through Rho and Rac to polarize and stabilize mediolateral protrusions (Tahinci and Symes, 2003). Moreover, the effects of RhoA and Rac disruption on cell intercalation behaviors do not parallel those observed in single migrating cells (Nobes and Hall, 1995; Tahinci and Symes, 2003). Together, these data suggest the effect of PCP on mediolaterally-positioned protrusions could be indirect. One possible mediator is the septin cytoskeleton, as septins are enriched mediolaterally in PCP dependent manner in the Xenopus gastrula mesoderm (Kim et al., 2010). Moreover, septins are required for convergent extension and their loss disrupts actin dynamics at the mediolateral faces of intercalating cells (Kim et al., 2010; Shindo and Wallingford, 2014). Ultimately, the relationship between PCP, Rho GTPases, and cellular protrusive activity remains an important unresolved issue.

PCP-independent cell intercalation in Drosophila

Though PCP signaling governs cell intercalation in both vertebrates and invertebrates, it is not required for cell intercalation in the Drosophila germ band (Zallen and Wieschaus, 2004), and these cells are polarized through an alternative molecular mechanism. Initial studies of Drosophila convergent extension showed that the pair-rule gene family were required for extension of the AP axis (Irvine and Wieschaus, 1994). The pair-rule genes form a distinct, striped pattern that underlies patterning of the AP axis in Drosophila, and these genes are also required for polarized localization of contractile myosin to v-junctions (Zallen and Wieschaus, 2004). Curiously, though pair-rule genes are not conserved in vertebrates, cell intercalation in Xenopus is nonetheless dependent upon proper AP patterning (Ninomiya et al., 2004) and PCP signaling components do accumulate at AP cell interfaces (Butler and Wallingford, 2018; Ciruna et al., 2006; Ossipova et al., 2015; Yin et al., 2008) providing another common thread linking intercalation in divergent settings.

The direct connection between the pair-rule genes and actomyosin polarization has emerged only recently, with the observation that pair-rule genes drive the patterned and alternating expression of three Toll receptors; toll-2, toll-6, and toll-8 (Paré et al., 2014). Toll receptors, well known in forming immune response to bacterial infection, are integral membrane proteins capable of forming homo- and heterotypic adhesions (Kawai and Akira, 2010). In Drosophila, the three Toll receptors form overlapping and alternating stripes along the AP axis (Paré et al., 2014), and this alternating pattern results in homotypic adhesion at mediolateral cell interfaces and heterotypic adhesion at AP cell interfaces (Paré et al., 2014). These heterotypic interactions in turn drive actomyosin accumulation and contraction at the v-junctions. Polarity is further reinforced by exclusion of contractile actomyosin at t-junctions, where receptors form homotypic interactions (Tetley et al., 2016). A role for Toll receptors in PCP-dependent cell intercalation has not been reported, but it is noteworthy that control of the Rho GTPase is also critical for cell intercalation in Drosophila (Sun et al., 2017), as it is in frogs and mice (Habas et al., 2003; Ybot-Gonzalez et al., 2007b). Given the unified cellular mechanism described above, it is tempting to speculate that additional molecular similarities will emerge with further study.

Mechanisms of force production during junction shrinking

The major differences between 2D single cell migration and intercalation are the substrate and the location of force production. Migrating cells apply traction force against the ECM through focal adhesions (Balaban et al., 2001). During migration, actin is specifically polymerized at the leading edge of the cell (Ridley et al., 2003). Polymerization of actin at the leading edge generates retrograde flow of actin filaments that catch ECM-bound focal adhesions, producing a traction force against the ECM (Gardel et al., 2010). Binding of actin to focal adhesions stops retrograde flow, resulting in the formation of forward-directed lamellipodia and filopodia, and then establishment of new leading edge adhesions allows forward movement (Gardel et al., 2010). All of this occurs concurrently with retraction of the cell’s lagging edge, where polarized Rho signaling directs actomyosin contractility and disassembly of focal adhesions, allowing forward movement (Ridley et al., 2003). Together, traction and protrusion at the front and contraction at the back provide the force for cell migration (Ridley et al., 2003). It is worth noting that for simplicity, our discussion here focuses on the idealized migration of a single cell on a 2D ECM, though cells can employ alternative mechanisms to migrate in complex extracellular environments (Charras and Sahai, 2014), in confined spaces, in the absence of ECM and integrin adhesion (Paluch et al., 2016), or as collectives (Mayor and Etienne-Manneville, 2016).

The forces driving cell intercalation are less well defined, but have been characterized at shrinking v-junctions in epithelial tissues, where traction forces are applied directly to neighboring cells through cell-cell junctions. Here, it was initially proposed that polarization of contractile actomyosin generates anisotropic force to shrink v-junctions (Bertet et al., 2004; Zallen and Wieschaus, 2004). Mathematical modeling and cell junction ablation experiments supported this model, showing increased tension at v-junctions (Rauzi et al., 2008). Similar experiments in the Xenopus mesoderm also report that increased tension at v-junctions is associated with actomyosin enrichment (Shindo and Wallingford, 2014). Moreover, v-junction localized multicellular myosin II cables are required for rosette formation (Fernandez-Gonzalez et al., 2009). However, while there is strong evidence for increased tension at v-junctions, it is not clear if this tension is entirely the result of actomyosin contractility at the v-junction as tissue scale forces may contribute to this the v-junction tension.

There is also increasing evidence that oscillations of contractile machinery are important to cell intercalations. Epithelial cells display oscillations in apical surface area and actomyosin contractility machinery and these oscillatory behaviors precede cell intercalation (Fernandez-Gonzalez and Zallen, 2011). Moreover, there are two pools of contractile actomyosin in Drosophila epithelial cells; “junctional” myosin at cell-cell contacts and “medial” myosin at the apical surface (Martin et al., 2009). During Drosophila convergent extension the medial pools of myosin flow from the apical surface to v-junctions and these flows correlate with junction shrinking (Rauzi et al., 2010; Sawyer et al., 2011). As well polarized junctional myosin is required to maintain junction length after an oscillatory shrinking event (Munjal et al., 2015). Taken together, a ratchet mechanism has now been proposed: oscillatory flows of medial actin provide the force for junction shrinking and polarized pools of junctional actin maintain junction length between flows (Munjal et al., 2015).

Curiously, two populations of oscillating actomyosin have also been described in mesenchymal cells in Xenopus, a superficially-positioned “node and cable” network (Kim and Davidson, 2011; Pfister et al., 2016; Skoglund et al., 2008) and a deeper cortical population (Shindo and Wallingford, 2014). In this light, it is also of interest that in addition to their spatially asymmetric enrichment, PCP proteins also display temporally dynamic patterns of localization. Specifically, both Prickle and Vangl proteins display oscillatory enrichment at shrinking junctions, and these oscillations are tightly linked to actomyosin oscillations in both epithelial and mesenchymal cells in Xenopus (Butler and Wallingford, 2018; Shindo et al., 2018). Given that cytoskeletal oscillators have also been shown to drive individual cell migration (Huang et al., 2013), it is clear that their roles in morphogenesis require additional attention (Gorfinkiel, 2015).

Force production at protrusions: Is there a “leading edge” in cell intercalation?

Polarization of actomyosin machinery and generation of anisotropic force is a central feature of eukaryotic cell movement, and in single migrating cells it begins with an external cue that results in asymmetric enrichment of lipids (eg. phosphatidylinositols) and signaling molecules (eg. Rho family GTPases) to the leading and lagging edges of the cell (Etienne-Manneville and Hall, 2002; Iijima and Devreotes, 2002). At the leading edge, this molecular polarity interfaces with the cytoskeleton through recruitment of actin nucleators, which produce waves of actin polymerization in the direction of cellular movement (Graziano and Weiner, 2014). The waves of actin polymerization are then sustained and amplified by complex feedback mechanisms that integrate signaling cascades, actin polymerization and dissociation rates, and membrane tension and curvature (Graziano and Weiner, 2014). As the actin polymerizes forward, it binds to focal adhesions, producing traction force on the ECM to move the cell forward (Ridley et al., 2003). Simultaneously, at the lagging edge of the cell, focal adhesions are disengaged and actomyosin contractility machinery pull the rear of the cell forward (Gardel et al., 2010; Lauffenburger and Horwitz, 1996; van Helvert et al., 2018).

The relationship between this better characterized mechanism for polarization in single cells and that in cell intercalation remains unclear. Strictly speaking, there seems to be no “leading” edge in cell intercalation, because protrusions are bipolar and the axis of individual cell movement is perpendicular to the axis of bulk tissue deformation. Thus, rather than a front-toback polarity, intercalation requires polarization of the entire population within the plane of the tissue (Tada and Heisenberg, 2012). Nonetheless, the bipolar protrusions are enriched for actin and the phosphatidylinositides PIP3 (Sun et al., 2017), and require the activity of the Rho family GTPases (Habas et al., 2003; Habas et al., 2001; Tahinci and Symes, 2003), suggesting that polarization of the bipolar protrusions may be at least somewhat similar to the leading edge of migrating cells.

Another outstanding question about cell intercalation relates to how these protrusions exert force during intercalation. It seems satisfying to think that these protrusions behave in the same manner as the leading edge of a migrating cell, crawling on ECM, but it is not clear that this is the case. It was initially proposed that these protrusions were grabbing neighbor cells and pulling them together to drive intercalation (Shih and Keller, 1992a), and this model was supported by the fact that explants of amphibian mesoderm can intercalate and extend in the absence of any ECM or substrate to crawl on (Keller, 2012). Moreover, it has been shown that protrusions can form cell-cell adhesions with neighbor cells and that these adhesions are regulated by actomyosin contractility (Pfister et al., 2016). However it has also been shown that integrin α5β1 is required for polarized protrusions and that the ECM is actively remodeled during cell intercalation (Davidson et al., 2004; Davidson et al., 2006). With evidence supporting force production at points of cell contact and the ECM, it will be interesting (and important) to determine exactly where protrusions are generating traction force during cell intercalation.

Finally, intercalating mesenchymal cells in Xenopus do have seemingly unique contractile actomyosin structures, termed “nodes and cables,” spanning the cytoplasm between the bipolar lamellipodia (Kim and Davidson, 2011; Pfister et al., 2016; Skoglund et al., 2008). The nodes and cables represent distinct actomyosin networks that undergo contractile pulses concurrently with shape changes in the cell, and disruption of the nodes and cables disrupts cell intercalation (Kim and Davidson, 2011). Determining the exact role of cellular protrusions during intercalation will provide great insight into the cellular mechanism of intercalation and is currently one of the most outstanding questions in the field.

Conclusion

Here, we have tried to integrate diverse findings in several species and tissues into a “unified field theory” for cell intercalation during convergent extension. We propose that mediolaterally-positioned bipolar protrusions work in concert with active shrinkage of AP cell faces in both epithelial cells and mesenchymal cells. We further argue that while junction shrinking and cell crawling may provide larger or smaller contributions in different settings, a combination of the two is a shared feature of PCP-mediated convergent extension in vertebrates and PCP-independent convergent extension in Drosophila.

In epithelia, it is clear that these two cellular mechanisms are spatially distinct, with apical junction shrinking complementing basal cell crawling (Sun et al., 2017; Williams et al., 2014). Perhaps the biggest outstanding question, then, relates to the integration of cell crawling and junction shrinking in mesenchymal cells. These cells do not display apicobasal polarity and both crawling by protrusions and shrinking by actomyosin contraction have been observed to span the deep/superficial axis of these cells (Kim and Davidson, 2011; Shindo and Wallingford, 2014). We can envision two possibilities, and these are not mutually exclusive: First, it may be that the two mechanisms are spatially separated, with contraction and protrusive cell crawling acting simultaneously, but restricted to very local regions along the junction. Alternatively, the two may be temporally separated, with periods of junction shrinking interspaced with periods of cell crawling. Imaging with higher temporal and spatial resolution will be required to address this question. Other outstanding questions relate to the interplay between developmental signals (e.g. PCP, Toll receptors) and the fundamental machinery of cell movement (e.g. actin assembly, cadherin adhesion, etc.). Genetic interactions observed between PCP proteins and the actin regulators Cofilin and Wdr1 (Blair et al., 2006; Luxenburg et al., 2015; Mahaffey et al., 2013) may provide an entry point for such explorations.

These unanswered questions remind us that our understanding of cell intercalation lags far behind that of single cell migration, a gap that is important because of the clinical relevance of convergent extension. It is abundantly clear that mutations in PCP genes cause neural tube defects in humans (Juriloff and Harris, 2012; Wallingford et al., 2013), and human embryos with severe neural tube defects display evidence of severely disrupted convergent extension (Kirillova et al., 2000; Marin-Padilla, 1966). Moreover, convergent extension is critical for limb morphogenesis (Li et al., 2017; Wang et al., 2011), and PCP genes are strongly implicated in human skeletal dysplasias (Bunn et al., 2015; White et al., 2018). It is our hope that this Perspective, and the models discussed here for convergent extension will motivate further exploration.

Acknowledgements

The models proposed here grew from extensive conversations between the authors and Lance Davidson and Ray Keller at the Cold Spring Harbor Labs course on Cell and Developmental Biology of Xenopus; the work would have been impossible without such collegiality and institutional support. We also thank Shinuo Weng, Caitlin Devitt, Jen Zallen and Margot Williams for critical discussions and their equally collegial spirit. This work was supported by grants to J.B.W from the NICHD and NIGMS.

Footnotes

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References:

  1. Andreeva A, Lee J, Lohia M, Wu X, Macara, Ian G., and Lu, X. (2014). PTK7-Src Signaling at Epithelial Cell Contacts Mediates Spatial Organization of Actomyosin and Planar Cell Polarity. Developmental Cell 29, 20–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Balaban NQ, Schwarz US, Riveline D, Goichberg P, Tzur G, Sabanay I, Mahalu D, Safran S, Bershadsky A, Addadi L, et al. (2001). Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nature Cell Biology 3, 466. [DOI] [PubMed] [Google Scholar]
  3. Bertet C, Sulak L, and Lecuit T (2004). Myosin-dependent junction remodelling controls planar cell intercalation and axis elongation. Nature 429, 667–671. [DOI] [PubMed] [Google Scholar]
  4. Blair A, Tomlinson A, Pham H, Gunsalus KC, Goldberg ML, and Laski FA (2006). Twinstar, the Drosophila homolog of cofilin/ADF, is required for planar cell polarity patterning. Development 133, 1789–1797. [DOI] [PubMed] [Google Scholar]
  5. Blankenship JT, Backovic ST, Sanny JS, Weitz O, and Zallen JA (2006). Multicellular rosette formation links planar cell polarity to tissue morphogenesis. Dev Cell 11, 459–470. [DOI] [PubMed] [Google Scholar]
  6. Bunn KJ, Daniel P, Rosken HS, O’Neill AC, Cameron-Christie SR, Morgan T, Brunner HG, Lai A, Kunst HP, Markie DM, et al. (2015). Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome. American journal of human genetics 96, 623–630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Butler M, and Wallingford JB (2018). Spatial and temporal PCP protein dynamics coordinate cell intercalation during neural tube closure. bioRxiv. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Butler MT, and Wallingford JB (2017). Planar cell polarity in development and disease. Nature Reviews Molecular Cell Biology 18, 375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Charras G, and Sahai E (2014). Physical influences of the extracellular environment on cell migration. Nature Reviews Molecular Cell Biology 15, 813. [DOI] [PubMed] [Google Scholar]
  10. Ciruna B, Jenny A, Lee D, Mlodzik M, and Schier AF (2006). Planar cell polarity signalling couples cell division and morphogenesis during neurulation. Nature 439, 220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Collazo A, Bronner-Fraser M, and Fraser SE (1993). Vital dye labelling of Xenopus laevis trunk neural crest reveals multipotency and novel pathways of migration. Development 118, 363. [DOI] [PubMed] [Google Scholar]
  12. Davidson LA, Keller R, and DeSimone DW (2004). Assembly and remodeling of the fibrillar fibronectin extracellular matrix during gastrulation and neurulation in Xenopus laevis. Developmental Dynamics 231, 888–895. [DOI] [PubMed] [Google Scholar]
  13. Davidson LA, Marsden M, Keller R, and DeSimone DW (2006). Integrin α 5 β 1 and fibronectin regulate polarized cell protrusions required for Xenopus convergence and extension. Current biology 16, 833–844. [DOI] [PubMed] [Google Scholar]
  14. Devenport D (2016). Tissue morphodynamics: Translating planar polarity cues into polarized cell behaviors. Seminars in Cell & Developmental Biology 55, 99–110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Etienne-Manneville S, and Hall A (2002). Rho GTPases in cell biology. Nature 420, 629. [DOI] [PubMed] [Google Scholar]
  16. Even-Ram S, and Yamada KM (2005). Cell migration in 3D matrix. Current Opinion in Cell Biology 17, 524–532. [DOI] [PubMed] [Google Scholar]
  17. Fernandez-Gonzalez R, Simoes Sde M, Roper JC, Eaton S, and Zallen JA (2009). Myosin II dynamics are regulated by tension in intercalating cells. Dev Cell 17, 736–743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fernandez-Gonzalez R, and Zallen JA (2011). Oscillatory behaviors and hierarchical assembly of contractile structures in intercalating cells. Physical biology 8, 045005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ffrench-Constant C, Van de Water L, Dvorak HF, and Hynes RO (1989). Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J Cell Biol 109, 903–914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gardel ML, Schneider IC, Aratyn-Schaus Y, and Waterman CM (2010). Mechanical Integration of Actin and Adhesion Dynamics in Cell Migration. Annual Review of Cell and Developmental Biology 26, 315–333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gorfinkiel N (2015). From actomyosin oscillations to tissue‐level deformations. Developmental Dynamics 245, 268–275. [DOI] [PubMed] [Google Scholar]
  22. Graziano BR, and Weiner OD (2014). Self-organization of protrusions and polarity during eukaryotic chemotaxis. Current Opinion in Cell Biology 30, 60–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Greene NDE, Gerrelli D, Van Straaten HWM, and Copp AJ (1998). Abnormalities of floor plate, notochord and somite differentiation in the loop-tail (Lp) mouse: a model of severe neural tube defects. Mechanisms of Development 73, 59–72. [DOI] [PubMed] [Google Scholar]
  24. Guirao B, and Bellaïche Y (2017). Biomechanics of cell rearrangements in Drosophila. Current Opinion in Cell Biology 48, 113–124. [DOI] [PubMed] [Google Scholar]
  25. Habas R, Dawid IB, and He X (2003). Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation. Genes & Development 17, 295–309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Habas R, Kato Y, and He X (2001). Wnt/Frizzled Activation of Rho Regulates Vertebrate Gastrulation and Requires a Novel Formin Homology Protein Daam1. Cell 107, 843–854. [DOI] [PubMed] [Google Scholar]
  27. Hay ED (2005). The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Developmental Dynamics 233, 706–720. [DOI] [PubMed] [Google Scholar]
  28. Heisenberg C-P, Tada M, Rauch G-J, Saude L, Concha ML, Geisler R, Stemple DL, Smith JC, and Wilson SW (2000). Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature 405, 76–81. [DOI] [PubMed] [Google Scholar]
  29. Huang C-H, Tang M, Shi C, Iglesias PA, and Devreotes PN (2013). An excitable signal integrator couples to an idling cytoskeletal oscillator to drive cell migration. Nature Cell Biology 15, 1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Huttenlocher A, and Horwitz AR (2011). Integrins in Cell Migration. Cold Spring Harbor Perspectives in Biology 3, a005074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Iijima M, and Devreotes P (2002). Tumor Suppressor PTEN Mediates Sensing of Chemoattractant Gradients. Cell 109, 599–610. [DOI] [PubMed] [Google Scholar]
  32. Irvine KD, and Wieschaus E (1994). Cell intercalation during Drosophila germband extension and its regulation by pair-rule segmentation genes. Development 120, 827–841. [DOI] [PubMed] [Google Scholar]
  33. Juriloff DM, and Harris MJ (2012). A consideration of the evidence that genetic defects in planar cell polarity contribute to the etiology of human neural tube defects. Birth Defects Research Part A: Clinical and Molecular Teratology 94, 824–840. [DOI] [PubMed] [Google Scholar]
  34. Kawai T, and Akira S (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunology 11, 373. [DOI] [PubMed] [Google Scholar]
  35. Keller R (2002). Shaping the Vertebrate Body Plan by Polarized Embryonic Cell Movements. Science 298, 1950. [DOI] [PubMed] [Google Scholar]
  36. Keller R (2012). Physical biology returns to morphogenesis. Science 338, 201–203. [DOI] [PubMed] [Google Scholar]
  37. Keller R, and Tibbetts P (1989). Mediolateral cell intercalation in the dorsal, axial mesoderm of Xenopus laevis. Developmental Biology 131, 539–549. [DOI] [PubMed] [Google Scholar]
  38. Keller RAY, and Hardin J (1987). Cell Behaviour During Active Cell Rearrangement: Evidence and Speculations. Journal of Cell Science 1987, 369. [DOI] [PubMed] [Google Scholar]
  39. Keys DN, Levine M, Harland RM, and Wallingford JB (2002). Control of Intercalation Is Cell-Autonomous in the Notochord of Ciona intestinalis. Developmental Biology 246, 329–340. [DOI] [PubMed] [Google Scholar]
  40. Kim HY, and Davidson LA (2011). Punctuated actin contractions during convergent extension and their permissive regulation by the non-canonical Wnt-signaling pathway. Journal of Cell Science 124, 635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kim SK, Shindo A, Park TJ, Oh EC, Ghosh S, Gray RS, Lewis RA, Johnson CA, Attie-Bittach T, Katsanis N, et al. (2010). Planar Cell Polarity Acts Through Septins to Control Collective Cell Movement and Ciliogenesis. Science 329, 1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kirillova I, Novikova I, Auge J, Audollent S, Esnault D, Encha-Razavi F, Lazjuk G, Attie-Bitach T, and Vekemans M (2000). Expression of the sonic hedgehog gene in human embryos with neural tube defects. Teratology 61, 347–354. [DOI] [PubMed] [Google Scholar]
  43. Lauffenburger DA, and Horwitz AF (1996). Cell Migration: A Physically Integrated Molecular Process. Cell 84, 359–369. [DOI] [PubMed] [Google Scholar]
  44. Li Y, Li A, Junge J, and Bronner M (2017). Planar cell polarity signaling coordinates oriented cell division and cell rearrangement in clonally expanding growth plate cartilage. eLife 6, e23279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Lienkamp SS, Liu K, Karner CM, Carroll TJ, Ronneberger O, Wallingford JB, and Walz G (2012). Vertebrate kidney tubules elongate using a planar cell polarity-dependent, rosette-based mechanism of convergent extension. Nat Genet 44, 1382–1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Luxenburg C, Heller E, Pasolli HA, Chai S, Nikolova M, Stokes N, and Fuchs E (2015). Wdr1-mediated cell shape dynamics and cortical tension are essential for epidermal planar cell polarity. Nat Cell Biol 17, 592–604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Mahaffey JP, Grego-Bessa J, Liem KF Jr., and Anderson KV (2013). Cofilin and Vangl2 cooperate in the initiation of planar cell polarity in the mouse embryo. Development 140, 1262–1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Marin-Padilla M (1966). STUDY OF THE VERTEBRAL COLUMN IN HUMAN CRANIORHACHISCHISIS. Cells Tissues Organs 63, 32–48. [DOI] [PubMed] [Google Scholar]
  49. Marlow F, Topczewski J, Sepich D, and Solnica-Krezel L (2002). Zebrafish Rho Kinase 2 Acts Downstream of Wnt11 to Mediate Cell Polarity and Effective Convergence and Extension Movements. Current Biology 12, 876–884. [DOI] [PubMed] [Google Scholar]
  50. Martin AC, Kaschube M, and Wieschaus EF (2009). Pulsed contractions of an actin-myosin network drive apical constriction. Nature 457, 495–499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Mayor R, and Etienne-Manneville S (2016). The front and rear of collective cell migration. Nature Reviews Molecular Cell Biology 17, 97. [DOI] [PubMed] [Google Scholar]
  52. Munjal A, Philippe JM, Munro E, and Lecuit T (2015). A self-organized biomechanical network drives shape changes during tissue morphogenesis. Nature 524, 351–355. [DOI] [PubMed] [Google Scholar]
  53. Neumann NM, Perrone MC, Veldhuis JH, Huebner RJ, Zhan H, Devreotes PN, Brodland GW, and Ewald AJ (2018). Coordination of Receptor Tyrosine Kinase Signaling and Interfacial Tension Dynamics Drives Radial Intercalation and Tube Elongation. Developmental Cell 45, 67–82.e66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Ninomiya H, Elinson RP, and Winklbauer R (2004). Antero-posterior tissue polarity links mesoderm convergent extension to axial patterning. Nature 430, 364. [DOI] [PubMed] [Google Scholar]
  55. Nishimura T, Honda H, and Takeichi M (2012). Planar Cell Polarity Links Axes of Spatial Dynamics in Neural-Tube Closure. Cell 149, 1084–1097. [DOI] [PubMed] [Google Scholar]
  56. Nobes CD, and Hall A (1995). Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62. [DOI] [PubMed] [Google Scholar]
  57. Ossipova O, Kim K, and Sokol SY (2015). Planar polarization of Vangl2 in the vertebrate neural plate is controlled by Wnt and Myosin II signaling. Biology Open 4, 722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Paluch EK, Aspalter IM, and Sixt M (2016). Focal Adhesion–Independent Cell Migration. Annual Review of Cell and Developmental Biology 32, 469–490. [DOI] [PubMed] [Google Scholar]
  59. Paré AC, Vichas A, Fincher CT, Mirman Z, Farrell DL, Mainieri A, and Zallen JA (2014). A positional Toll receptor code directs convergent extension in Drosophila. Nature 515, 523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Pfister K, Shook DR, Chang C, Keller R, and Skoglund P (2016). Molecular model for force production and transmission during vertebrate gastrulation. Development 143, 715–727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Rauzi M, Lenne PF, and Lecuit T (2010). Planar polarized actomyosin contractile flows control epithelial junction remodelling. Nature 468, 1110–1114. [DOI] [PubMed] [Google Scholar]
  62. Rauzi M, Verant P, Lecuit T, and Lenne PF (2008). Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis. Nat Cell Biol 10, 1401–1410. [DOI] [PubMed] [Google Scholar]
  63. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, and Horwitz AR (2003). Cell migration: integrating signals from front to back. Science 302, 1704–1709. [DOI] [PubMed] [Google Scholar]
  64. Sawyer JK, Choi W, Jung KC, He L, Harris NJ, and Peifer M (2011). A contractile actomyosin network linked to adherens junctions by Canoe/afadin helps drive convergent extension. Molecular biology of the cell 22, 2491–2508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Sedzinski J, Hannezo E, Tu F, Biro M, and Wallingford JB (2016). Emergence of an Apical Epithelial Cell Surface In Vivo. Dev Cell 36, 24–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Shah PK, Tanner MR, Kovacevic I, Rankin A, Marshall TE, Noblett N, Tran NN, Roenspies T, Hung J, Chen Z, et al. (2017). PCP and SAX-3/Robo Pathways Cooperate to Regulate Convergent Extension-Based Nerve Cord Assembly in C. elegans. Developmental Cell 41, 195–203.e193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Shih J, and Keller R (1992a). Cell motility driving mediolateral intercalation in explants of Xenopus laevis. Development 116, 901. [DOI] [PubMed] [Google Scholar]
  68. Shih J, and Keller R (1992b). Patterns of cell motility in the organizer and dorsal mesoderm of Xenopus laevis. Development 116, 915. [DOI] [PubMed] [Google Scholar]
  69. Shindo A (2018). Models of convergent extension during morphogenesis. Wiley Interdisciplinary Reviews: Developmental Biology 7, e293–n/a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Shindo A, Inoue Y, Kinoshita M, and Wallingford JB (2018). Frequency and synchrony of actomyosin oscillation during PCP-dependent convergent extension. bioRxiv. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Shindo A, and Wallingford JB (2014). PCP and septins compartmentalize cortical actomyosin to direct collective cell movement. Science 343, 649–652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Skoglund P, Rolo A, Chen X, Gumbiner BM, and Keller R (2008). Convergence and extension at gastrulation require a myosin IIB-dependent cortical actin network. Development 135, 2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Strutt DI (2002). The asymmetric subcellular localisation of components of the planar polarity pathway. Seminars in Cell & Developmental Biology 13, 225–231. [DOI] [PubMed] [Google Scholar]
  74. Strutt DI, Weber U, and Mlodzik M (1997). The role of RhoA in tissue polarity and Frizzled signalling. Nature 387, 292. [DOI] [PubMed] [Google Scholar]
  75. Sun Z, Amourda C, Shagirov M, Hara Y, Saunders TE, and Toyama Y (2017). Basolateral protrusion and apical contraction cooperatively drive Drosophila germ-band extension. Nat Cell Biol 19, 375–383. [DOI] [PubMed] [Google Scholar]
  76. Szabó A, Cobo I, Omara S, McLachlan S, Keller R, and Mayor R (2016). The Molecular Basis of Radial Intercalation during Tissue Spreading in Early Development. Developmental Cell 37, 213–225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Tada M, and Heisenberg CP (2012). Convergent extension: using collective cell migration and cell intercalation to shape embryos. Development 139, 3897–3904. [DOI] [PubMed] [Google Scholar]
  78. Tada M, and Smith JC (2000). Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway. Development 127, 2227. [DOI] [PubMed] [Google Scholar]
  79. Tahinci E, and Symes K (2003). Distinct functions of Rho and Rac are required for convergent extension during Xenopus gastrulation. Developmental Biology 259, 318–335. [DOI] [PubMed] [Google Scholar]
  80. Tetley RJ, Blanchard GB, Fletcher AG, Adams RJ, and Sanson B (2016). Unipolar distributions of junctional Myosin II identify cell stripe boundaries that drive cell intercalation throughout Drosophila axis extension. eLife 5, e12094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Trichas G, Smith AM, White N, Wilkins V, Watanabe T, Moore A, Joyce B, Sugnaseelan J, Rodriguez TA, Kay D, et al. (2012). Multi-Cellular Rosettes in the Mouse Visceral Endoderm Facilitate the Ordered Migration of Anterior Visceral Endoderm Cells. PLOS Biology 10, e1001256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. van Helvert S, Storm C, and Friedl P (2018). Mechanoreciprocity in cell migration. Nature Cell Biology 20, 8–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Vogt W (1922). Die Einrollung und steckung der urmundlippen bei Triton nach versuchenmit einer neuen mthode embrynalere trans- plantation. Deutch Zool Gesell, 49–51. [Google Scholar]
  84. Walck-Shannon E, and Hardin J (2014). Cell Intercalation from top to bottom. Nature reviews Molecular cell biology 15, 34–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Wallingford JB, Niswander LA, Shaw GM, and Finnell RH (2013). The Continuing Challenge of Understanding, Preventing, and Treating Neural Tube Defects. Science 339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Wallingford JB, Rowning BA, Vogeli KM, Rothbacher U, Fraser SE, and Harland RM (2000). Dishevelled controls cell polarity during Xenopus gastrulation. Nature 405, 81–85. [DOI] [PubMed] [Google Scholar]
  87. Wang B, Sinha T, Jiao K, Serra R, and Wang J (2011). Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B. Human molecular genetics 20, 271–285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. White JJ, Mazzeu JF, Coban-Akdemir Z, Bayram Y, Bahrambeigi V, Hoischen A, van Bon BWM, Gezdirici A, Gulec EY, Ramond F, et al. (2018). WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. American journal of human genetics 102, 27–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Williams M, Yen W, Lu X, and Sutherland A (2014). Distinct apical and basolateral mechanisms drive PCP-dependent convergent extension of the mouse neural plate. Developmental cell 29, 34–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Williams MLK, and Solnica-Krezel L (2017). Regulation of gastrulation movements by emergent cell and tissue interactions. Current Opinion in Cell Biology 48, 33–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Williams-Masson EM, Heid PJ, Lavin CA, and Hardin J (1998). The Cellular Mechanism of Epithelial Rearrangement during Morphogenesis of theCaenorhabditis elegansDorsal Hypodermis. Developmental Biology 204, 263–276. [DOI] [PubMed] [Google Scholar]
  92. Wilson P, and Keller R (1991). Cell rearrangement during gastrulation of Xenopus: direct observation of cultured explants. Development 112, 289. [DOI] [PubMed] [Google Scholar]
  93. Winter CG, Wang B, Ballew A, Royou A, Karess R, Axelrod JD, and Luo L (2001). Drosophila Rho-Associated Kinase (Drok) Links Frizzled-Mediated Planar Cell Polarity Signaling to the Actin Cytoskeleton. Cell 105, 81–91. [DOI] [PubMed] [Google Scholar]
  94. Ybot-Gonzalez P, Savery D, Gerrelli D, Signore M, Mitchell CE, Faux CH, Greene ND, and Copp AJ (2007a). Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Development 134, 789–799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Ybot-Gonzalez P, Savery D, Gerrelli D, Signore M, Mitchell CE, Faux CH, Greene NDE, and Copp AJ (2007b). Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Development 134, 789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Yen WW, Williams M, Periasamy A, Conaway M, Burdsal C, Keller R, Lu X, and Sutherland A (2009). PTK7 is essential for polarized cell motility and convergent extension during mouse gastrulation. Development 136, 2039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Yin C, Kiskowski M, Pouille P-A, Farge E, and Solnica-Krezel L (2008). Cooperation of polarized cell intercalations drives convergence and extension of presomitic mesoderm during zebrafish gastrulation. The Journal of Cell Biology 180, 221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Zallen JA, and Wieschaus E (2004). Patterned gene expression directs bipolar planar polarity in Drosophila. Dev Cell 6, 343–355. [DOI] [PubMed] [Google Scholar]

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