How do the atypical cadherins Fat and Dachsous integrate growth and patterning during development?

How do the organs in our body control their shape and size? We know that when they fail to do this, we get overgrowth, and frequently cancer. If we can understand these control systems, perhaps we will be able to understand what happens when tissues overgrow and go on to develop more effective treatments. Proper growth control requires the coordinated movements and rearrangements of many cells and so these cells must have mechanisms to communicate with each other. Interestingly, it is now understood that if the cells within an organ can coordinate with one another to build a sense of direction, this helps them to regulate their shape and size. However, we don't know how this sense of direction coordinates with the growth control mechanisms. In the past, the fruit fly wing has been used successfully to study coordinated growth control, revealing many parallels to human growth control. For example, the proteins Fat and Dachsous are known to regulate tissue shape and size both in flies and humans. We plan to do experiments in the fruit fly wing to study how Fat and Dachsous function. We will also use computational models, which describe these processes mathematically, to put our experimental evidence together and help us to understand these mechanisms. We can then use these computational models to make predictions about how the system should behave if we manipulate it in some way. We can then test these predictions by doing further experiments, which will allow us to decide if the original assumptions were correct and ultimately understand how growth and direction are coordinated.

A fundamental problem in developmental biology is to understand how growth and patterning are coordinated to form tissues of the correct shape and size. To achieve this, growth must be coordinated with the axes of the tissue. In Drosophila epithelia, the atypical cadherins Fat (Ft) and Dachsous (Ds) regulate such anisotropic growth. This function is conserved to humans where misregulation of homologous proteins leads to epithelial cancers, such as oral, gastric or breast cancer, and congenital defects such as cardiac mitral valve prolapse.

In Drosophila tissues, planar polarisation of Ft and Ds - guided by tissue-level expression patterns - directs growth in an oriented manner. However, how Ft and Ds interpret tissue-level information is disputed. There are two hypotheses: one depends on graded expression of an upstream regulatory molecule - Four-jointed (Fj) - in the presumptive wing region; the other on a moving boundary of high Ds expression on the edge of the growing wing tissue.

These hypotheses make different predictions regarding: i) the spatial patterns of Ds and Fj required to generate Ft-Ds polarity; ii) the temporal response of Ft-Ds polarity to changes in Fj/Ds spatial patterns; and iii) the role of growth in the establishment and maintenance of Ft-Ds polarity. We propose to test each of these predictions experimentally through spatiotemporal genetic manipulation of Ds and Fj expression patterns during wing development. In tandem, we will build computational models to rationalise, refine and test our hypotheses.

Due to caveats, neither hypothesis appears sufficient to explain polarisation across a large growing tissue. Thus, we speculate that a combination of the two may be necessary. Our integrative approach will allow us to determine the relative contributions of each mechanism over time. This will give us an integrated view of how the Ft-Ds pathway interprets tissue-level gene expression patterns and coordinates this with tissue growth.

Beneficiaries:
1. Future patients suffering from cancer: The proposed study is most relevant to carcinomas, which derive from epithelial cells, covering 80% of known primary cancers. During this project we propose to study the function of known tumour-suppressor molecules, Fat and Dachsous, which are mutated in breast, brain, gastric and oral cancers. Basic biomedical research has a translation timescale of 20+ years. However, we will proactively seek out opportunities for collaborations with clinical research to build on the research in this proposal. Timescale: 1-3+ years.
2. Industry: We will develop new software modules that will be integrated into the open-source Chaste platform and made freely available for download under the 3-clause software BSD license. Chaste is a general-purpose simulation package aimed at computationally demanding multiscale problems arising in biology and physiology. Taking advantage of the recently established Research Software Engineering service (Department of Computer Science), we will ensure that new modules are fully tested and of high quality before incorporation into the Chaste package. Mathematical model implementations, including datasets used for parameterisation and validation, will be freely available to download as a Chaste 'bolt-on' project and GitHub branch.
- Generate new code functionality. Timescale: 6 months.
- Develop, parameterise and validate model implementations. Timescale: 2-3 years.
3. Those recruiting scientifically trained staff, including business, industrial and public sector: Group members supported by this grant will improve their training, including transferable skills, e.g. project management and leadership skills. Additionally, we will supervise undergraduate/postgraduate students, contributing to their training in scientific experimentation, experimental design, data analysis, and transferable skills. Thus, this grant will contribute towards the health of UK science and higher education through developing expertise and training highly skilled researchers. Timescale: 1-3+ years.
4. The public: The team will communicate the importance, excitement and beauty of scientific research to the public, e.g. by presenting at our Institute-wide events such as Researchers' Night and Festival of the Mind. Examining molecular and cellular behaviour in living animals provides beautiful images that effectively capture and communicate the concepts of biomedicine. Timescale: 1-3 years.