Shellard, Adam; (2018) The biomechanics of collective neural crest cell chemotaxis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Collective cell migration underlies various events in development, regeneration and disease. In most cases in vivo, collective migration occurs by collective cell chemotaxis, the directed migration of cell groups along gradients of soluble chemical cues. Despite this, the mechanisms of collective cell chemotaxis are poorly understood. Here I use Xenopus and zebrafish neural crest, a highly migratory embryonic stem cell population whose behaviour has been likened to malignant invasion, to study collective chemotaxis ex vivo and in vivo. I show that the neural crest exhibits a tensile actomyosin ring at the edge of the migratory cell group that contracts in a supracellular fashion. This contractility is polarized during collective cell chemotaxis: it is inhibited at the front but persists at the rear of the cell cluster. Combining computational simulations with optogenetic and laser ablation experiments, I show that this differential contractility drives directed collective cell migration ex vivo and in vivo through intercalation of rear cells. Rear cell intercalation triggers a wave of cellular anterograde movement through the middle of the cluster that drives the whole group forward. The mechanically coupled cells at the edge of the group are pulled to the rear by the actomyosin contractility. This novel mechanism of collective cell chemotaxis can be conceptually visualized as squeezing a tube of tooth paste at the back, which pushes the toothpaste forward. Thus, in neural crest cells, the engine for collective chemotaxis is at the rear of the cell group. Surprisingly, many of the cell behaviours that I describe here for the whole cell cluster have an equivalent in directional migration of single cells. For example, contraction of rear cells within a cluster is equivalent to actomyosin contraction at the back of single cells during directional migration; retrograde movement of cells in the periphery of the cluster could correspond to the surface/cortex retrograde flow observed in single cells; and rear intercalation and forward movement of cells at the centre of the cluster is analogous to rear endocytosis and forward movement of vesicles in single cells. In summary, I have discovered a novel mechanism of collective cell migration in which we can consider the whole cluster as a single ‘supracell’.

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