Mathematical modelling of growth control in Drosophila development

Lead Research Organisation: Imperial Cancer Research Fund
Department Name: London Research Institute (LIF)

Abstract

Have you ever wondered why your hands are the size they are? Or why some people have bigger hands, but they are almost identical in shape and proportion to your hands? The control of organ growth is highly complex, but highly important, as when the control system fails, we get overgrowth, and frequently cancer. How does the organ know when to stop growing? How does it control its shape? If we can understand this, perhaps we will be able to understand what happens when tissues over grow, and treat the problem (e.g. cancer) at its source. Many biologists have successfully used the Drosophila wing as a model to study growth control, revealing many parallels to human growth control. I hope to put all these data, the pieces of a puzzle, together, into a mathematical/computer model and eventually make a virtual wing. I‘ll be able to compare the relative importance of the different control mechanisms, something that‘s quite hard to do via experiments. I may find that internal control is key, and the environment plays little role, or vice versa. I can also model different cancerous conditions, and quickly test treatments before deciding whether they are worth trying experimentally/clinically.

Technical Summary

How tissue size is controlled is a fundamental biological question that remains remarkably ill-understood. The development of organs of appropriate size and shape depends both on the extent and orientation of growth. This project aims to understand how tissue growth is sensed and restricted in vivo. I propose to use a combination of mathematical modelling and experimental approaches, using Drosophila development as a model system.

The imaginal discs are the precursors to the Drosophila adult appendages. Since they are flat epithelial sheets during much of development, imaginal discs are highly suitable for mathematical modelling. In addition, imaginal discs can readily be manipulated genetically to study the loss- or gain-of-function for any gene. Together with live imaging of cultured imaginal discs, I will be able to monitor the dynamics of cells in wild type and various mutant imaginal discs.

In Drosophila wing imaginal discs, the orientation of cell elongation and cell division predominantly along the proximo-distal (PD) axis determines the elongated shape of the wing. Recent evidence suggests that proteins controlling planar cell polarity such as Fat (Ft), Dachsous (Ds), and Dachs are able to co-ordinately regulate both growth rates and growth orientation. Of particular interest, Dachs protein is asymmetrically localised along the PD axis, with higher levels on the distal side. Since Dachs is an atypical myosin, does it restrict membrane growth by contracting the membrane where it is localised, thereby promoting cell elongation and therefore cell division along the PD axis? To answer this question, I will build a model of a 2D field of cells that grow and divide according to experimentally derived rules and parameters for wild type tissue. I can compare virtual clonal experiments with live developing clones. Through experimentation, I will measure the necessary parameters, such as tensile strength of Dachs, amounts of Dachs, and rates of membrane elongation (live movies). I can also easily expand my model to include more factors, and study how gradients of various morphogens in the wing can affect the localisation of Dachs and growth orientation.

This interdisciplinary research should allow us to study more accurately the dynamics of growth orientation and to formulate and test less intuitive hypotheses to reveal new insights into the mechanisms of growth control. Given the fact that tissue overgrowth is the cause of human cancer, I hope that this project will have an impact on cancer as well as developmental biology.

Publications

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Title EpiTools: a new open source image analysis platform 
Description A new modular software that allows automatic segmentation and tracking of time lapse images for epithelial tissue development. 
Type Of Material Improvements to research infrastructure 
Year Produced 2014 
Provided To Others? Yes  
Impact Quantitative data /image analysis has been made possible, saving potentially thousands of hours of human work time. Still to be published and publicly available. 
 
Title Tissue stretcher and compressor 
Description A novel method / research tool / device that allows the stretching or compressing of tissues during in vitro culturing 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact Has allowed the assessment of the impact of direct physical force on developing tissues, which was not possible before. Novel findings yet to be consolidated and published. 
 
Title EpiTools: a new open source image analysis platform 
Description A modular image analysis pipeline that allows automatic segmentation and tracking of live imaging data for epithelial tissues 
Type Of Material Data analysis technique 
Year Produced 2014 
Provided To Others? Yes  
Impact Has allowed high throughput data analysis of time lapse data. 
 
Description EpiTools: a new open source image analysis platform 
Organisation Kingston University London
Country United Kingdom 
Sector Academic/University 
PI Contribution Created the original concept/problem, provided experimental data, started developing the image analysis software.
Collaborator Contribution Provided further technical input into developing the software and creating a user friendly platform
Impact Paper published in Dev Cell 2016. An open source software will be available. Multiple disciplines: developmental biology, imaging, image analysis, computer vision
Start Year 2011
 
Description EpiTools: a new open source image analysis platform 
Organisation University of Zurich
Country Switzerland 
Sector Academic/University 
PI Contribution Created the original concept/problem, provided experimental data, started developing the image analysis software.
Collaborator Contribution Provided further technical input into developing the software and creating a user friendly platform
Impact Paper published in Dev Cell 2016. An open source software will be available. Multiple disciplines: developmental biology, imaging, image analysis, computer vision
Start Year 2011
 
Description Mathematical modelling 
Organisation Cancer Research UK
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Carried out experiments, some of which were used to build and test the model. I learnt computational modelling and built the computational model together with the collaborator
Collaborator Contribution Helped me build my mathematical / computational model for my project
Impact A paper has just been accepted (not published yet) in Genes and Development. Collaboration is multidisciplinary: maths, computer modelling, biophysics, genetics, cell biology
Start Year 2009
 
Description Tissue Stretcher - effect of exogenous force on tissue growth and morphogenesis 
Organisation Curie Institute Paris (Institut Curie)
Country France 
Sector Academic/University 
PI Contribution We created the concept of making a versatile tissue stretcher and compressor device and designed the novel system and device.
Collaborator Contribution My partners have assisted with PDMS micro patterning techniques and the making of a prototype of a first version of the tissue stretcher. They are also helping with making force measurements on the wing disc tissue.
Impact A publication for this new technique is currently being prepared, and we are also seeking patenting options. Multiple disciplines for this research: biophysics, nanotechnology, cell biology, developmental biology
Start Year 2011
 
Description Tissue Stretcher - effect of exogenous force on tissue growth and morphogenesis 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We created the concept of making a versatile tissue stretcher and compressor device and designed the novel system and device.
Collaborator Contribution My partners have assisted with PDMS micro patterning techniques and the making of a prototype of a first version of the tissue stretcher. They are also helping with making force measurements on the wing disc tissue.
Impact A publication for this new technique is currently being prepared, and we are also seeking patenting options. Multiple disciplines for this research: biophysics, nanotechnology, cell biology, developmental biology
Start Year 2011