Figure 1: The zebrafish migrating lateral line organ allows collective migration to be easily studied in vivo.
Figure 2: Visualising actin dynamics (LifeAct-GFP) within migrating primordium.
Using the zebrafish as a model, the Gilmour group takes an integrative, multiscale approach to study how cells collectively migrate and assemble into functional organs.
Previous and Current Research
Collective behaviour lies at the heart of all biological design. Whether it is the assembly of proteins into complexes or the organisation of animal societies, collective interaction creates something much greater than the sum of the parts. What about cells? Cell biology has told us a great deal about how individual cells are organised but very little about how they form complex tissues and organs. This is because the standard culture systems that are the cell biologists’ workhorse have been selected for uniformity, but they lack interesting collective behaviour.
By contrast, studies on developing embryos are revealing a picture where every decision a cell makes – from the genes it expresses to the shape it adopts – depends on dynamic interactions with other cells. And while studies on embryos provide a more complex view of cell and tissue morphogenesis – where heterogeneous cells shape each other through dynamic interactions – this approach provides a number of opportunities for cell biology. For example, using embryonic systems we can hopefully understand how cellular organisation feeds back on the genome to drive differentiation. Moreover, a precise understanding of how cells organise each other could accelerate the use of tissue engineering approaches in human healthcare.
We are taking an integrative, multiscale approach to study how cells collectively migrate and assemble into functional organs, using the zebrafish lateral line organ as a model. Here, a migrating epithelial primordium comprising 100 cells assembles and deposits a series of rosette-like mechanosensory organs. We chose it for a number of reasons: it is a complete organogenesis process that takes place on a remarkably small spatiotemporal scale; its superficial migration route, beneath a single transparent cell layer, makes it the dream in vivo sample for quantitative imaging approaches; genetic screens have identified regulators of its behaviour that are of great interest due to their role in human disease – for example, it is guided by Cxcr4/SDF1 signalling, a chemokine-receptor pair known to control many human cancers.
Future Projects and Goals
We have developed in vivo imaging and analysis tools that allow an entire morphogenesis process to be addressed at different spatiotemporal scales. By integrating these data using statistical multiplexing methods, we are able to unequivocally define the relationship between different tissue behaviours (such as motility and shape) and explain these at the level of underlying machinery (such as actin dynamics and chemokine signalling). Such correlations are subsequently validated using acute perturbation experiments and the data are combined using computational modelling approaches. As much of what we find is likely to be applicable in other contexts, we hope to move towards a systems-level understanding of the interplay between gene activity, cell organisation and tissue mechanics during tissue morphogenesis.