Eric Theveneau

Collective Chemotaxis Requires Contact-Dependent Cell Polarity

Summary Directional collective migration is now a widely recognized mode of migration during embryogenesis and cancer. However, how a cluster of cells responds to chemoattractants is not fully understood. Neural crest cells are among the most motile cells in the embryo, and their behavior has been likened to malignant invasion. Here, we show that neural crest cells are collectively attracted toward the chemokine Sdf1. While not involved in initially polarizing cells, Sdf1 directionally stabilizes cell protrusions promoted by cell contact. At this cell contact, N-cadherin inhibits protrusion and Rac1 activity and in turn promotes protrusions and activation of Rac1 at the free edge. These results show a role for N-cadherin during contact inhibition of locomotion, and they reveal a mechanism of chemoattraction likely to function during both embryogenesis and cancer metastasis, whereby attractants such as Sdf1 amplify and stabilize contact-dependent cell polarity, resulting in directional collective migration.

Neural crest delamination and migration: From epithelium-to-mesenchyme transition to collective cell migration

After induction and specification in the ectoderm, at the border of the neural plate, the neural crest (NC) population leaves its original territory through a delamination process. Soon afterwards, the NC cells migrate throughout the embryo and colonize a myriad of tissues and organs where they settle and differentiate. The delamination involves a partial or complete epithelium-to-mesenchyme transition (EMT) regulated by a complex network of transcription factors including several proto-oncogenes. Studying the relationship between these genes at the time of emigration, and their individual or collective impact on cell behavior, provides valuable information about their role in EMT in other contexts such as cancer metastasis. During migration, NC cells are exposed to large number of positive and negative regulators that control where they go by generating permissive and restricted areas and by modulating their motility and directionality. In addition, as most NC cells migrate collectively, cell-cell interactions play a crucial role in polarizing the cells and interpreting external cues. Cell cooperation eventually generates an overall polarity to the population, leading to directional collective cell migration. This review will summarize our current knowledge on delamination, EMT and migration of NC cells using key examples from chicken, Xenopus, zebrafish and mouse embryos. Given the similarities between neural crest migration and cancer invasion, these cells may represent a useful model for understanding the mechanisms of metastasis.

Complement Fragment C3a Controls Mutual Cell Attraction during Collective Cell Migration

Summary Collective cell migration is a mode of movement crucial for morphogenesis and cancer metastasis. However, little is known about how migratory cells coordinate collectively. Here we show that mutual cell-cell attraction (named here coattraction) is required to maintain cohesive clusters of migrating mesenchymal cells. Coattraction can counterbalance the natural tendency of cells to disperse via mechanisms such as contact inhibition and epithelial-to-mesenchymal transition. Neural crest cells are coattracted via the complement fragment C3a and its receptor C3aR, revealing an unexpected role of complement proteins in early vertebrate development. Loss of coattraction disrupts collective and coordinated movements of these cells. We propose that coattraction and contact inhibition act in concert to allow cell collectives to self-organize and respond efficiently to external signals, such as chemoattractants and repellents.

Chase-and-run between adjacent cell populations promotes directional collective migration

Collective cell migration in morphogenesis and cancer progression often involves the coordination of multiple cell types. How reciprocal interactions between adjacent cell populations lead to new emergent behaviours remains unknown. Here we studied the interaction between neural crest (NC) cells, a highly migratory cell population, and placodal cells, an epithelial tissue that contributes to sensory organs. We found that NC cells chase placodal cells by chemotaxis, and placodal cells run when contacted by NC. Chemotaxis to Sdf1 underlies the chase, and repulsion involving PCP and N-cadherin signalling is responsible for the run. This chase-and-run requires the generation of asymmetric forces, which depend on local inhibition of focal adhesions. The cell interactions described here are essential for correct NC migration and for segregation of placodes in vivo and are likely to represent a general mechanism of coordinated migration.

The neural crest

The neural crest (NC) is a highly migratory multipotent cell population that forms at the interface between the neuroepithelium and the prospective epidermis of a developing embryo. Following extensive migration throughout the embryo, NC cells eventually settle to differentiate into multiple cell types, ranging from neurons and glial cells of the peripheral nervous system to pigment cells, fibroblasts to smooth muscle cells, and odontoblasts to adipocytes. NC cells migrate in large numbers and their migration is regulated by multiple mechanisms, including chemotaxis, contact-inhibition of locomotion and cell sorting. Here, we provide an overview of NC formation, differentiation and migration, highlighting the molecular mechanisms governing NC migration.

Cadherins in collective cell migration of mesenchymal cells

Immunity, embryogenesis and tissue repair rely heavily on cell migration. Cells can be seen migrating as individuals or large groups. In the latter case, collectiveness emerges via cell-cell interactions. In migratory epithelial cell sheets, classic Cadherins are critical to maintain tissue integrity, to promote coordination and establish cell polarity. However, recent evidence indicates that mesenchymal cells, migrating in streams such as neural crest or cancer cells, also exhibit collective migration. Here we will explore the idea that Cadherins play an essential role during collective migration of mesenchymal cells.

Cadherin Switch during EMT in Neural Crest Cells Leads to Contact Inhibition of Locomotion via Repolarization of Forces

Summary Contact inhibition of locomotion (CIL) is the process through which cells move away from each other after cell-cell contact, and it contributes to malignant invasion and developmental migration. Various cell types exhibit CIL, whereas others remain in contact after collision and may form stable junctions. To investigate what determines this differential behavior, we study neural crest cells, a migratory stem cell population whose invasiveness has been likened to cancer metastasis. By comparing pre-migratory and migratory neural crest cells, we show that the switch from E- to N-cadherin during EMT is essential for acquisition of CIL behavior. Loss of E-cadherin leads to repolarization of protrusions, via p120 and Rac1, resulting in a redistribution of forces from intercellular tension to cell-matrix adhesions, which break down the cadherin junction. These data provide insight into the balance of physical forces that contributes to CIL in cells in vivo.

Ets-1 Confers Cranial Features on Neural Crest Delamination

Neural crest cells (NCC) have the particularity to invade the environment where they differentiate after separation from the neuroepithelium. This process, called delamination, is strikingly different between cranial and trunk NCCs. If signalings controlling slow trunk delamination start being deciphered, mechanisms leading to massive and rapid cranial outflow are poorly documented. Here, we show that the chick cranial NCCs delamination is the result of two events: a substantial cell mobilization and an epithelium to mesenchyme transition (EMT). We demonstrate that ets-1, a transcription factor specifically expressed in cranial NCCs, is responsible for the former event by recruiting massively cranial premigratory NCCs independently of the S-phase of the cell cycle and by leading the gathered cells to straddle the basal lamina. However, it does not promote the EMT process alone but can cooperate with snail-2 (previously called slug) to this event. Altogether, these data lead us to propose that ets-1 plays a pivotal role in conferring specific cephalic characteristics on NCC delamination.

Collective cell migration of epithelial and mesenchymal cells

Directional cell migration is required for proper embryogenesis, immunity, and healing, and its underpinning regulatory mechanisms are often hijacked during diseases such as chronic inflammations and cancer metastasis. Studies on migratory epithelial tissues have revealed that cells can move as a collective group with shared responsibilities. First thought to be restricted to proper epithelial cell types able to maintain stable cell–cell junctions, the field of collective cell migration is now widening to include cooperative behavior of mesenchymal cells. In this review, we give an overview of the mechanisms driving collective cell migration in epithelial tissues and discuss how mesenchymal cells can cooperate to behave as a collective in the absence of bona fide cell–cell adhesions.

The role of the non-canonical Wnt–planar cell polarity pathway in neural crest migration

The neural crest is an embryonic stem cell population whose migratory behaviour has been likened to malignant invasion. The neural crest, as does cancer, undergoes an epithelial-to-mesenchymal transition and migrates to colonize almost all the tissues of the embryo. Neural crest cells exhibit collective cell migration, moving in streams of high directionality. The migratory neural crest streams are kept in shape by the presence of negative signals in their vicinity. The directionality of the migrating neural crest is achieved by contact-dependent cell polarization, in a phenomenon called contact inhibition of locomotion. Two cells experiencing contact inhibition of locomotion move away from each other after collision. However, if the cell density is high only cells exposed to a free edge can migrate away from the cluster leading to the directional migration of the whole group. Recent work performed in chicks, zebrafish and frogs has shown that the non-canonical Wnt-PCP (planar cell polarity) pathway plays a major role in neural crest migration. PCP signalling controls contact inhibition of locomotion between neural crest cells by localizing different PCP proteins at the site of cell contact during collision and locally regulating the activity of Rho GTPases. Upon collision RhoA (ras homologue family member A) is activated, whereas Rac1 is inhibited at the contact between two migrating neural crest cells, leading to the collapse of protrusions and the migration of cells away from one another. The present review summarizes the mechanisms that control neural crest migration and focuses on the role of non-canonical Wnt or PCP signalling in this process.