Top image

Gilmour GroupPublications

Quantitative cell polarity imaging defines leader-to-follower transitions during collective migration and the key role of microtubule-dependent adherens junction formation.
Revenu, C., Streichan, S., Dona, E., Lecaudey, V., Hufnagel, L. & Gilmour, D.
Development. 2014 Mar;141(6):1282-91. doi: 10.1242/dev.101675.
The directed migration of cell collectives drives the formation of complex organ systems. A characteristic feature of many migrating collectives is a 'tissue-scale' polarity, whereby 'leader' cells at the edge of the tissue guide trailing 'followers' that become assembled into polarised epithelial tissues en route. Here, we combine quantitative imaging and perturbation approaches to investigate epithelial cell state transitions during collective migration and organogenesis, using the zebrafish lateral line primordium as an in vivo model. A readout of three-dimensional cell polarity, based on centrosomal-nucleus axes, allows the transition from migrating leaders to assembled followers to be quantitatively resolved for the first time in vivo. Using live reporters and a novel fluorescent protein timer approach, we investigate changes in cell-cell adhesion underlying this transition by monitoring cadherin receptor localisation and stability. This reveals that while cadherin 2 is expressed across the entire tissue, functional apical junctions are first assembled in the transition zone and become progressively more stable across the leader-follower axis of the tissue. Perturbation experiments demonstrate that the formation of these apical adherens junctions requires dynamic microtubules. However, once stabilised, adherens junction maintenance is microtubule independent. Combined, these data identify a mechanism for regulating leader-to-follower transitions within migrating collectives, based on the relocation and stabilisation of cadherins, and reveal a key role for dynamic microtubules in this process.
Europe PMC

Directional tissue migration through a self-generated chemokine gradient.
Dona, E., Barry, J.D., Valentin, G., Quirin, C., Khmelinskii, A., Kunze, A., Durdu, S., Newton, L.R., Fernandez-Minan, A., Huber, W., Knop, M. & Gilmour, D.
Nature. 2013 Nov 14;503(7475):285-9. doi: 10.1038/nature12635. Epub 2013 Sep 25.
The directed migration of cell collectives is a driving force of embryogenesis. The predominant view in the field is that cells in embryos navigate along pre-patterned chemoattractant gradients. One hypothetical way to free migrating collectives from the requirement of long-range gradients would be through the self-generation of local gradients that travel with them, a strategy that potentially allows self-determined directionality. However, a lack of tools for the visualization of endogenous guidance cues has prevented the demonstration of such self-generated gradients in vivo. Here we define the in vivo dynamics of one key guidance molecule, the chemokine Cxcl12a, by applying a fluorescent timer approach to measure ligand-triggered receptor turnover in living animals. Using the zebrafish lateral line primordium as a model, we show that migrating cell collectives can self-generate gradients of chemokine activity across their length via polarized receptor-mediated internalization. Finally, by engineering an external source of the atypical receptor Cxcr7 that moves with the primordium, we show that a self-generated gradient mechanism is sufficient to direct robust collective migration. This study thus provides, to our knowledge, the first in vivo proof for self-directed tissue migration through local shaping of an extracellular cue and provides a framework for investigating self-directed migration in many other contexts including cancer invasion.
Europe PMC

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.
Europe PMC

EMT 2.0: shaping epithelia through collective migration.
Revenu, C. & Gilmour, D.
Curr Opin Genet Dev. 2009 Aug;19(4):338-42. Epub 2009 May 20.
Epithelial-mesenchymal transitions (EMTs) drive epithelial remodelling by converting cohesive, stable epithelial layers into individual, motile mesenchymal cells. It is now becoming clear that, from being an all-or-nothing switch, EMT can be applied in a fine-tuned manner to allow the efficient migration of cohesive epithelia that maintain their internal organisation. Recent work suggests that such collective motility involves a complex balance between epithelial and mesenchyme-like cell states that is driven by internal and external cues. Although this cohesive mode requires more complex control than single cell migration, it creates opportunities in term of tissue guidance and shaping that are starting to be unravelled.
Europe PMC

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.
Europe PMC