Modelling collective cell migration of neural crest

Abstract

Collective cell migration has emerged in the recent decade as an important phenomenon in cell and developmental biology and can be defined as the coordinated and cooperative movement of groups of cells. Most studies concentrate on tightly connected epithelial tissues, even though collective migration does not require a constant physical contact. Movement of mesenchymal cells is more independent, making their emergent collective behaviour less intuitive and therefore lending importance to computational modelling. Here we focus on such modelling efforts that aim to understand the collective migration of neural crest cells, a mesenchymal embryonic population that migrates large distances as a group during early vertebrate development. By comparing different models of neural crest migration, we emphasize the similarity and complementary nature of these approaches and suggest a future direction for the field. The principles derived from neural crest modelling could aid understanding the collective migration of other mesenchymal cell types.

Figure 1. Collective migration depends on internal and external factors

(a) Collective migration depends on interactions within the migrating collective (blue arrows) although external factors may also influence the movement, such as physical obstacles (brown arrows) or external gradients (orange arrows). (b) Collective versus coordinated migration: coordinated movement is simply the sum of the parts while collective movement depends on interactions within the group. (c-e) Examples of epithelial collective migration: (c) Border cells (light blue) during collective migration in the Drosophila ovary acquire outwards polarity due to interactions with “polar cells” (dark blue) within the cluster, while the whole cluster polarizes in the direction of an external chemoattractant gradient (indicated by red/green outlines). (d) Internal structure and interactions of the posterior lateral line primordium during collective migration in zebrafish development (lateral view of the cluster). The trailing population (light blue) sequesters the underlying chemoattractant (black arrow) generating a gradient that stimulates forward chemotaxis of the leader population (dark blue). In return the leaders secrete FGF that attracts the trailing cells. (e) Cell-cell interactions within epithelial sheets: during plithotaxis, cells move (blue arrows) within an epithelial sheet to minimize intercellular shear (red arrows). (f) Schematic representation of neural crest (NC) migration within the embryo. The NC differentiates and undergoes EMT at the borders of the neural plate and then invades the surrounding tissues, including placodes. During its migration the NC interacts with the ECM and external chemoattractants and maintains interactions within the migrating cluster. Migration occurs in the head first, where streams are wider and larger than at more posterior locations.

Figure 2. Main models of cranial neural crest migration.

(a) Follow-the-leader model of NC migration. Leader cells (dark blue) chemotax towards VEGF, unlike followers (light blue) that are moving towards the closest leader cell or a chain of followers led by a leader cell (Follow-the-leader, dark blue arrows). If a follower is not contacted by any other cell, it moves randomly until it contacts a leader of a chain. Sufficient exposure to VEGF gradient triggers follower-to-leader phenotype switch, while lack of a VEGF gradient leads to leader-to-follower switch. All cells sequester VEGF (black curved arrows), leading to a self-generated gradient from the initial uniformly high concentrations. (b) NC migration model based on co-attraction (CoA, dark blue arrows) and contact inhibition of locomotion (CIL, light blue arrows). The persistently moving cells secrete the chemoattractant C3a (dark blue rhomboids) leading to CoA. After contact the cells form adhesions via N-Cadherin (green boxes), align their movement, and subsequently repolarise and move away from one another (CIL). These interactions lead to a coherently migrating NC cluster.