Collective Cell Migration in Neural Crest Development

Abstract

The migration of multiple cells as a cooperative unit known as collective cell migration is a common phenomenon in development, cancer and healing. Cooperation can be implemented by physical and/or chemical means and thus happens in epithelial as well as mesenchymal cell populations. Neural crest cells, a highly motile embryonic population, are a well‐known model for epithelial–mesenchymal transition and cell migration. Neural crest cells use various strategies to cooperate and migrate collectively which make them a good model for the study of collectiveness. Further, neural crest cells' interaction with other embryonic populations also relies on cell cooperation, thus providing a model for the study of cell cooperation during organogenesis.

Key Concepts

  • Neural crest cells are migratory multipotent stem cells.
  • Neural crest cells distribute according to cell–cell and cell–environment interactions.
  • Some neural crest cell populations migrate collectively.
  • Collectiveness is based on cell–cell cooperation via paracrine chemotaxis and cell–cell adhesion.
  • Collectiveness influences cell guidance.
  • Cooperation takes place at several orders of magnitude: among neural crest cells and between neural crest cells and adjacent cell populations.

Keywords: collective migration; epithelial–mesenchymal transition; neural crest; directional migration; development; cell adhesion; cadherins; polarity; chemotaxis

Figure 1. Overview of neural crest development. (a) Dorsal view of a vertebrate embryo at early neurula stage, neural crest (NC) cells are lateral to the neural plate (NP). (b) Dorsal view of a vertebrate embryo at late neurula stage, NC cells are located along the midline. (c–e) Transversal sections showing the relative positions of the ectoderm, NC, NP and mesoderm at early neural stage (c), late neurula stage (d) and after neural crest emigration (e). (f–h) Dorsal views depicting the antero‐posterior wave of neural crest emigration. Note that neural crest cells rapidly organise in discrete streams around obstacles of chemical nature (i.e. mesenchyme adjacent to rhombomere 3 (r3) which is rich in semaphorin) or physical nature (i.e. the otic vesicle and the eyes). (i) Detail of the migration of the ventro‐medial trunk neural crest cells in between epithelial somites, through the sclerotome and aggregating to form ganglia of the peripheral nervous system. Anlagen of ganglia are marked by dotted circles. DRG, dorsal root ganglion; SG, sympathetic ganglion.
Figure 3. Neural emigration and dispersion. (a) Overview of the main driving forces of neural crest dissemination. Neural crest cells (blue) emerge from the dorsal neuroepithelium (blue) as a continuous wave of single cells at high cell density. They disperse through the extracellular space. During migration, they encounter various constraints in the environment that force them into organising in specific streams. In addition, positive signals may drive some neural crest subpopulations into specific niche. (b) Transversal section through the dorsal neural tube at the time of neural crest delamination. The process of EMT can be summarised in three main steps: loss of apical cell–cell junction, apical retraction and protrusion into the extracellular space. These steps need not happen in that order. This is followed by migration away from the neural tube. During this process, there is a quantitative and qualitative change of cadherin expression as well as dynamic regulation of Rho and Rac activities. (c) During migration, neural crest cells experience contact inhibition of locomotion (CIL) which controls cell polarity in a cell–cell contact‐dependent manner. The main steps of CIL are depicted here: cells colliding, formation of a transient contact involving cadherins N and 11, activation of Wnt/PCP and RhoA and repolarisation and migration in opposite direction.
Figure 2. Mechanisms of cell cooperation leading to collectiveness. (a) Diagram of a stream of migrating neural crest cells. Cells on the outskirts of the group may leave owing to contact inhibition of locomotion but eventually come back due to co‐attraction, see the main text for details. (b) Pseudo‐kymograph representing the dynamics of membranes of two adjacent cells within the group. Note that cells keep being attracted to one another by co‐attraction (C3a/C3aR pathway) and repelled upon contact via contact inhibition of locomotion (N‐cadherin‐Wnt/PCP‐RhoA‐ROCK pathway). These attraction–repulsion cycles maintain the migratory population dense but nonetheless fluid. (c) In cells located at the leading edge of the population, co‐attraction and contact inhibition set the polarity of small GTPases RhoA and Rac1 which is further modulated by chemotaxis downstream of Sdf1/Cxcr4. (d) In cells that are isolated from the group, there is no long‐lasting polarity due to the absence of repeated feedback from co‐attraction and contact inhibition. As such the effect of Sdf1 signalling on polarity is reduced. Consequently, migratory neural crest cells that do not travel at high cell density poorly chemotax.
Figure 4. Collective migration in cell populations interacting with neural crest cells. (a) Dorsal view of a Xenopus gastrula. Mesodermal cells invaginate underneath the ectoderm and the prospective neural plate and neural crest. (b) Sagittal section of a Xenopus gastrula. (c) Inset showing the collective migration of mesodermal cells underneath the neural plate/crest territory. Cells are polarised due to intercellular tensions mediated by C‐cadherin junctions building up from the leading edge down. (d) Lateral views of Xenopus embryos at late neurula stage showing the coordinated dorso‐ventral migration of neural crest cells expressing Cxcr4 and placodal cells expressing Sdf1. (e) Details of the neural crest–placode interaction. Neural crest cells are attracted to Sdf1 produced by the placodes. Upon physical contact, both cell types undergo contact inhibition of locomotion and retract their protrusions. Neural crest cells, being more migratory, fill the gap first. The cycle of attraction–repulsion repeats itself. The higher motility of neural crest cells creates a bias and generates directional movement of placodal cells away from neural crest cells. That displaces the source of Sdf1 and promotes further migration of the neural crest cells.
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Further Reading

Developmental Biology, Special Issue on Neural Crest (2012).

Hall BK and Hall BK (2009) The Neural Crest and Neural Crest Cells in Vertebrate Development and Evolution, 2nd edn. New York: Springer.

Trainor PA (2014) Neural Crest Cells: Evolution, Development and Disease. Amsterdam: Elsevier/AP.

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Theveneau, Eric, and Andrieu, Cyril(Jun 2015) Collective Cell Migration in Neural Crest Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025976]