Dynamic Fgf signaling couples morphogenesis and migration in the zebrafish lateral line primordium

Abstract

The collective migration of cells in the form of cohesive tissues is a hallmark of both morphogenesis and repair. The extrinsic cues that direct these complex migrations usually act by regulating the dynamics of a specific subset of cells, those at the leading edge. Given that normally the function of tissue migration is to lay down multicellular structures, such as branched epithelial networks or sensory organs, it is surprising how little is known about the mechanisms that organize cells behind the leading edge. Cells of the zebrafish lateral line primordium switch from mesenchyme-like leader cells to epithelial rosettes that develop into mechanosensory organs. Here, we show that this transition is regulated by an Fgf signaling circuit that is active within the migrating primordium. Point sources of Fgf ligand drive surrounding cells towards a 'non-leader' fate by increasing their epithelial character, a prerequisite for rosette formation. We demonstrate that the dynamic expression of Fgf ligands determines the spatiotemporal pattern of epithelialization underlying sensory organ formation in the lateral line. Furthermore, this work uncovers a surprising link between internal tissue organization and collective migration.

lef1 controls patterning and proliferation in the posterior lateral line system of zebrafish

“…As the trailing rosette separates from the primordium, a new rosette is formed by the leading cells. FGF signaling is required for the formation of rosettes (Nechiporuk and Raible, 2008;Lecaudey et al, 2008), and would act by triggering a mesenchymal/ epithelial transition that forces the migrating cells into an epithelial organization (Lecaudey et al, 2008). FGF activity in the trailing cells depends on beta-catenin activity in the leading cells of the primordium (Aman and Piotrowski, 2008).…”

A hybrid model of cell migration in zebrafish embryogenesis

“…In few hours postfertilization a total migration of the primordium begins from the head to the tail of the embryo at an estimated velocity (≈69 μm h −1 ) [5]. Subsequently, a cell transition, occurring in the rear of the migrating group, makes some cells epithelial-like (mesenchymal-epithelial transition) and rosette-shaped structures (proto-neuromasts) begin to emerge.…”

“…The neuromast formation, in the second stage, is regulated by two main chemotactic factors expressed by the primordium, the equivalent fibroblast growth factors FGF3-FGF10, and by their receptors FGFRs. FGF signal and its receptor are mutually exclusive: FGF3-FGF10 are broadly expressed in the leading region of the primordium and focused in one or two cells in the centre of the rosettes in the trailing region, on the other hand FGFR is expressed in the trailing region except the FGF sources [5]. This let us divide the cell population in two kinds: leader cells that produce FGF signal and follower cells that, activating the receptor FGFR, do not produce any signal.…”

“…Hence a new rosette is generated in a cyclic process. Finally, the leader-to-follower transition in the trailing region can be represented by three conditions: a low level of SDF-1a, a high level of FGF and an influence of lateral inhibition [5]. This last condition can be read here as follows: a cell that adopts the follower fate inhibits its immediate neighbouring cells from doing likewise.…”

“…In [2], starting from the results obtained in recent biological experiments [3][4][5], we have have proposed a hybrid mathematical model describing self-organizing cell migration in the morphogenesis of the posterior lateral line system (PLL) in the model organism of zebrafish (Danio rerio). The great interest for this sensory system and the need to formulate new mathematical theoretical models is motivated by its important role in the current scientific research, and by the still not complete understanding of the general mechanism for cells arranging and organization [5]. The lateral line is a fundamental sensory system, present in fish and amphibians, that extends from the head to the tail along each flank of the individual.…”