Developmental biology

Neural crest cell migration

We study the mechanisms underlying cell migration in the developing embryo, using a computational model developed in close collaboration with in vivo experiments in the chick cranial neural crest. Here, a stream of cells has to invade a target tissue and at the same time distribute along the migratory route. Cranial neural crest cells are known to seek out a chemoattractant (VEGF). However, the chemoattractant is uniformly produced. Our working hypothesis is that a chemotactic gradient is induced by the cells themselves through internalisation of chemoattractant. This is represented computationally within a hybrid model framework (discrete cells off-lattice, continuous chemoattractant) on a growing domain.

Previous work has indicated the need for two subpopulations of cells with different behaviours. The presence of these subpopulations was validated experimentally, both by gene profiling and by confirming model predictions for tissue transplantation experiments. Our focus is now to extend this modelling framework, incorporating realistic cell sensing and differences in cell cohesion recently observed experimentally. The goal is to identify critical cell behaviours that lead to robust multicellular neural crest migration. Together with our collaborators we plan experiments and then conduct them in parallel in vivo, in vitro and computationally. Experimental results parameterise and inform the simulations, which in turn help to interpret existing results and suggest new experiments. We repeat this cycle of hypothesis generation and testing iteratively with the aim of providing a framework generalizable to multicellular migration in different organisms.

 

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Key references
  • R. McLennan, L. Dyson, K. W. Prather, J. A. Morrison, R. E. Baker, P. K. Maini, P. M. Kulesa (2012). Multiscale mechanisms of cell migration during development: theory and experiment. Development 139:2935-2944. (eprints)

 

     

    Regulation of tissue size through patterned apoptosis

    Elucidating the dynamics of epithelial pattern repair is a key challenge to understanding the robustness underlying embryogenesis. To gain insight into this complex process, we are developing  a computational model of an epidermal larval segment in the Drosophila embryo. This work is being undertaken in an iterative manner in close collaboration with the Zartman lab (University of Notre Dame). The model couples a reaction-diffusion model of epidermal growth factor (EGFR) activity, a key morphogen in this system, to a vertex-based model of cell dynamics, cell shape changes, proliferation and apoptosis (cell death) within the segment. We are investigating various hypothesized mechanisms relating EGFR signalling and mechanical feedback to apoptosis and cell dynamics. Model validation and refinement will occur in combination with high-resolution live-imaging data of EGFR signalling, cell proliferation and apoptosis.

    Schematic of our data analysis pipeline for model validation

    WCMB members working in this area
    Collaborators
     
      Key references
        • A. M. Smith, R. E. Baker, D. Kay and P. K. Maini (2012). Incorporating chemical signalling factors into cell-based models of growing epithelial tissues. J. Math. Biol. 65(3):441–463. (eprints