Collective cell migration guided by dynamically maintained gradients.
Streichan, S.J., Valentin, G., Gilmour, D. & Hufnagel, L.
Phys Biol. 2011 Aug;8(4):045004. doi: 10.1088/1478-3975/8/4/045004. Epub 2011 Jul12.
How cell collectives move and deposit subunits within a developing embryo is a question of outstanding interest. In many cases, a chemotactic mechanism is employed, where cells move up or down a previously generated attractive or repulsive gradient of signalling molecules. Recent studies revealed the existence of systems with isotropic chemoattractant expression in the lateral line primordium of zebrafish. Here we propose a mechanism for a cell collective, which actively modulates an isotropically expressed ligand and encodes an initial symmetry breaking in its velocity. We derive a closed solution for the velocity and identify an optimal length that maximizes the tissues' velocity. A length dependent polar gradient is identified, its use for pro-neuromast deposition is shown by simulations and a critical time for cell deposition is derived. Experiments to verify this model are suggested.
Collective cell migration in morphogenesis, regeneration and cancer.
Friedl, P. & Gilmour, D.
Nat Rev Mol Cell Biol. 2009 Jul;10(7):445-57.
The collective migration of cells as a cohesive group is a hallmark of the tissue remodelling events that underlie embryonic morphogenesis, wound repair and cancer invasion. In such migration, cells move as sheets, strands, clusters or ducts rather than individually, and use similar actin- and myosin-mediated protrusions and guidance by extrinsic chemotactic and mechanical cues as used by single migratory cells. However, cadherin-based junctions between cells additionally maintain 'supracellular' properties, such as collective polarization, force generation, decision making and, eventually, complex tissue organization. Comparing different types of collective migration at the molecular and cellular level reveals a common mechanistic theme between developmental and cancer research.
Dynamic Fgf signaling couples morphogenesis and migration in the zebrafish lateral line primordium.
Lecaudey, V., Cakan-Akdogan, G., Norton, W.H. & Gilmour, D.
Development. 2008 Aug;135(16):2695-705. Epub 2008 Jul 3.
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.
The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b.
Valentin, G., Haas, P. & Gilmour, D.
Curr Biol. 2007 Jun 19;17(12):1026-31.
Tissue migration is a collective behavior that plays a key role in the formation of many organ systems [1-3]. Although tissue movements are guided by extrinsic cues, in many contexts, their receptors need to be active only at the leading edge to ensure morphogenesis [4-8]. This has led to the prevalent view that extrinsic signals exert their influence by controlling a small number of leader cells. The zebrafish lateral-line primordium is a cohesive cohort of over 100 cells that is guided through CXCR4-SDF1 signaling [9-11]. Recent work has shown that Cxcr4b activity is only required in cells at the very tip, raising the question of what controls cell behavior within trailing regions . Here, we present the first mutant in zebrafish SDF1a/CXCL12a and show, surprisingly, that the resultant phenotype is stronger than a null mutation in its cognate receptor, Cxcr4b, indicating the involvement of other SDF1a receptors. A candidate approach identified Cxcr7/RDC1, whose expression is restricted to cells behind the leading edge. Morpholino knockdown of Cxcr7 leads to a novel phenotype in which the migration of trailing cells is specifically affected, causing tissue stretching, a defect rescued by the reintroduction of wild-type cells specifically at the back of the primordium. Finally, we present evidence that Cxcr4b and Cxcr7 act independently to regulate group migration. We provide the first example where a single extrinsic guidance cue, SDF1a, directly controls the migration of both leading and trailing edges of a tissue through the activation of two independent receptors, CXCR4b and CXCR7.