Contributions of cell behaviours to dorsal closure in Drosophila abdomen

Despite recent progress, the regulation and coordination of cell behaviours during tissue development remain poorly understood. I seek to address this issue by using agent-based computational models to investigate the extent to which different cell behaviours contribute to dorsal closure during morphogenesis of the Drosophila adult abdominal epidermis.

Shaping of tissues and organs arises as a result of morphogenetic processes, which rely on the regulation and coordination of a multitude of cell behaviours. In this project, I will be focusing on the development of the Drosophila (fruit fly) adult abdominal epidermis, during which larval epithelial cells (LECs) are replaced by adult histoblast cells [1].

In vivo 4D microscopy (the study of live Drosophila) provides us with the means to collect data. Multi-scale mathematical models allow us to demonstrate our understanding of cell dynamics within a tissue and enable us to make predictions that can be compared to the data. However, due to assumptions that they involve, currently available models only provide limited insights.

One example of this is that most models represent cells as polygons, which have straight edges. However, during morphogenesis, it has been shown that cells can form curved, lamellipodia-like protrusions that they use to propel themselves forwards. To investigate the extent to which these protrusions affect cell migration, which has been shown to be essential for the normal closure of the adult epidermis [1], I aim to extend existing models, by including migration via lamellipodia.

I also aim to incorporate a distinction between the different ways in which cell death is regulated into my models. A previous study found that inhibiting histoblast proliferation led to a delay in LEC death, suggesting that there exists a mechanism which coordinates these processes [2]. However, the study did not conclude what this mechanism relies on.

Mathematical modelling gives us the opportunity to investigate the relationship between the different events which regulate cell death, namely contact, mechanical signals and chemical signals, and the mechanism identified in [2].

In terms of mechanical signals, data has shown that local tissue mechanics impact the likelihood that a cell will delaminate (a way that cells are removed from the epithelia), which usually then leads to cell death [3]. Previous research has shown that most LECs do not die until after the histoblast nests (initially, histoblasts are clustered together in 'nests') start to expand [1].

Given this background, I am to investigate the hypothesis that mechanical forces arising from histoblast nest expansion causes delamination and then death of LECs.

I will be using the cell-based computational framework Chaste [4] as this will enable me to model individual cell behaviour. Starting with a simple model, I will design image analysis and inference algorithms to quantify behaviours observed experimentally. This can then be compared to the model outcomes, highlighting where adjustments should be made.

I will continue with this cycle of model alterations and experimental validation until my model represents the full range of cell dynamics in a tissue.

Genetic tools in Drosophila can be used to experimentally manipulate the system, which allows varying hypotheses to be tested. By manipulating individual model parameters, I can compare these results, which will highlight how the hypothesis should be updated. This interplay between model and experimental data will be vital.

The complex reshaping of tissue that my models will describe is representative of similar phenomena in higher organisms. Therefore, due to the high genetic similarity between organisms, the tools I develop will be relevant to the study of human health - particularly wound healing [5] and tumour growth [6], as these processes also rely on both cell death and changes in migratory behaviour.