Leading and trailing cells cooperate in collective migration of the zebrafish posterior lateral line primordium

Abstract

Collective migration of cells in the zebrafish posterior lateral line primordium (PLLp) along a path defined by Cxcl12a expression depends on Cxcr4b receptors in leading cells and on Cxcr7b in trailing cells. Cxcr7b-mediated degradation of Cxcl12a by trailing cells generates a local gradient of Cxcl12a that guides PLLp migration. Agent-based computer models were built to explore how a polarized response to Cxcl12a, mediated by Cxcr4b in leading cells and prevented by Cxcr7b in trailing cells, determines unidirectional migration of the PLLp. These chemokine signalingbased models effectively recapitulate many behaviors of the PLLp and provide potential explanations for the characteristic behaviors that emerge when the PLLp is severed by laser to generate leading and trailing fragments. As predicted by our models, the bilateral stretching of the leading fragment is lost when chemokine signaling is blocked in the PLLp. However, movement of the trailing fragment toward the leading cells, which was also thought to be chemokine dependent, persists. This suggested that a chemokine-independent mechanism, not accounted for in our models, is responsible for this behavior. Further investigation of trailing cell behavior shows that their movement toward leading cells depends on FGF signaling and it can be re-oriented by exogenous FGF sources. Together, our observations reveal the simple yet elegant manner in which leading and trailing cells coordinate migration; while leading cells steer PLLp migration by following chemokine cues, cells further back play follow-the-leader as they migrate toward FGFs produced by leading cells.

Epithelial cell behaviours during neurosensory organ formation

“…These results favour the following model: Cxcl12a and Cxcr4b interact at the leading edge to drive migration of the primordium, with availability (i.e. a threshold) of Cxcl12a rather than a gradient being necessary for migration; the role of Cxcr7b is to prevent more posteriorly localized Cxcr4b receptors from having access to Cxcl12a, hence preventing activity levels that are sufficient to induce cell protrusions (Dalle Nogare et al, 2014).…”

“…In both cases, it is unclear how the chemokine gradient regulates the migration of the trailing zone. A recent study has attempted to dissect these models (Dalle Nogare et al, 2014). In a primordium with abrogated Cxcr4b activity, the transplantation of a few Cxcr4b cells is sufficient to restore the migration of the primordium, only when the Cxcr4b cells are positioned at the leading edge (as leader cells; Haas and Gilmour, 2006).…”

“…In a primordium with abrogated Cxcr4b activity, the transplantation of a few Cxcr4b cells is sufficient to restore the migration of the primordium, only when the Cxcr4b cells are positioned at the leading edge (as leader cells; Haas and Gilmour, 2006). In addition, when Cxcl12a expression is ectopically induced in the entire primordium, protrusive (mesenchymal-like) cells are localized around the entire leading part of the primordium, yet the trailing cells remain unresponsive (Dalle Nogare et al, 2014). These results favour the following model: Cxcl12a and Cxcr4b interact at the leading edge to drive migration of the primordium, with availability (i.e.…”

“…Based on these experiments and observations, the dependence of leading and trailing regions on chemokine signalling has also been simulated using agent-based modelling (Dalle Nogare et al, 2014). These simulations could explain the chemokine-dependent behaviour of the leading domain but could not recapitulate the migratory behaviour of trailing cells.…”

Collective cell migration in development

“…Laser ablation of front cells or pharmacological inhibition of FGF receptor both result in the inability of trailing cells to migrate directionally, whereas inhibitor washout restores protrusive ability of the trailing fragment, which is then able to make contact with the leading end of the primordium and resume coordinated migration (Fig. 4 b; Dalle Nogare et al, 2014). Similar to the zebrafish lateral line, SDF-1 is expressed in a uniform manner in tissues surrounding the neural crest (Theveneau et al, 2010).…”