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Studying mechanisms underlying dynamic changes in cell behaviour during morphogenesis

Reference	BB/M021084/1
Principal Investigator / Supervisor	Dr Marcus Bischoff
Co-Investigators / Co-Supervisors
Institution	University of St Andrews
Department	Biology
Funding type	Research
Value (£)	442,112
Status	Completed
Type	Research Grant
Start date	01/10/2015
End date	31/03/2020
Duration	54 months

Abstract

The great variety of shapes of multicellular organisms arises during morphogenesis, when cells implement complex information to build tissues and organs accurately. Here, various cell behaviours, such as migration, shape changes and divisions, have to work together. Despite recent progress, it is still mysterious how this remarkable coordination is achieved and how the cytoskeletal activity that drives it is orchestrated. We propose to study the morphogenesis of the adult abdominal epidermis of Drosophila to gain insights into the mechanisms underlying the coordination and regulation of cell behaviours. Using a combination of in vivo 4D microscopy and sophisticated genetic tools will allow us to manipulate the system and study cell behaviours quantitatively, using bespoke software tools. We will focus on investigating cell migration and apical constriction of the larval epithelial cells (LECs). This will allow us (1) to identify and study signals that regulate and coordinate migration and constriction and (2) to analyse the mechanisms underlying dynamic change in behaviour, as LECs switch from migration to constriction. We will analyse cytoskeletal activity during this behavioural change and its relationship with cellular polarity as well as with Rho GTPase activity. Moreover, we will ask what signals are instructing this change. To study cytoskeletal activity we will characterise pulsed contractions that LECs show during morphogenesis. Tackling these questions will enable us to gain a deeper understanding of how cell behaviours are orchestrated and cytoskeletal activity is regulated. Such an understanding is of widespread relevance, since (mis-) regulation of cell behaviour is fundamental to wound repair and numerous diseases including cancer. Conservation across species means that the principles learned from our system will be applicable to mammals.

Summary

The diversity of shapes of multicellular organisms is astounding. Even more fascinating is that this diversity arises from a single cell. Initially, this cell divides into a ball of cells, and only a process known as morphogenesis will then give this mass a shape, which can be as different as a worm or a human. During morphogenesis, individual cells show a range of behaviours that ultimately lead to the formation of tissues and organs. For example, cells need to migrate to their position in the developing animal or change their shape. Importantly, cells need to communicate with each other to do so. Problems with these processes are evident in many medical conditions; most importantly, cancer cells abnormally change their behaviour to become mobile and cause metastases. Furthermore, cell migration is fundamental to wound healing, where cells move to close a wound. Our research project is aimed at understanding how such cell behaviours are regulated and coordinated. To investigate this problem, we use a simple model system, the fruit fly Drosophila, where we can study the behaviour of cells and tissues in the living animal as they undergo morphogenesis. Using Drosophila for our experiments also allows us to take advantage of the many features that make the fruit fly a very good model system, such as fast life cycle, powerful genetics and sophisticated time-lapse 4D microscopy of the living organism. At the same time, the fact that 75% of all disease causing genes are similar between flies and humans means that our discoveries will be relevant for humans. We will combine approaches that allow us to study the behaviour of individual cells in the developing tissue using 4D microscopy, with techniques that allow us to knock out a particular gene in just a few cells. This will enable us to identify signals that regulate and coordinate cell migration and cell shape change and to study the mechanisms underlying this regulation. Tackling these questions will enable us to gaina deeper understanding of morphogenetic processes and their underlying cell behaviours. These insights will be important for uncovering how cell behaviour is (mis-) regulated during wound healing and cancer.

Impact Summary

Academic impact Scientists working in academia and industry will benefit from the advances in our understanding of the regulation and coordination of cell behaviour and how cell behaviour is driven by cytoskeletal activity and instructed by planar cell polarity. Furthermore, colleagues will benefit from software development and refinement conducted during the course of this project. Economical and social impact Although the proposed research is fundamental basic biology, it has the potential to impact on human health. 75% of all disease causing genes are similar between Drosophila and humans, making our work potentially relevant. During tumour progression, cancer cells change their behaviour to become mobile and subsequently form metastases. During wound healing, epithelial cells become mobile to close the wound. Thus, insights into the mechanisms underlying the (mis-) regulation of cell behaviours gained during the course of this project will potentially help to tackle both cancer and tissue repair. Our screen for regulators of cell behaviour might in the long run help to identify drug targets for cancer or wound treatment. Outreach and engagement The public will benefit from outreach and engagement activities linked to this application. We are committed to activities supporting the public understanding of science. We will keep an updated website with a lay summary outlining relevance of our work and potential for future exploitation. We will furthermore participate in the Fife Science Festival and other outreach activities organised by the University. I will offer 'taster placements' to local pupils in my lab and give talks in local schools to stimulate the pupils' enthusiasm about nature and science. I will also deliver a yearly lecture at the St Andrews International Science Summer School. I will organise an exhibition of images themed on microscopy in St Andrews to engage the public, making use of the beauty of scientific discovery. Training research and professional skills Academia and the general job market will benefit from the training of the two co-workers supported by this project. I will teach my co-workers various techniques (e.g. Drosophila genetics, 4D microscopy and quantitative biology), scientific method and general problem solving skills. Providing training in advanced microscopy methods may prompt some of my trainees to enter R&D in optical technology. Furthermore, my co-workers will have access to the award winning "Gradskills" courses run by the University of St Andrews, which aim to provide a wide variety of transferable skills. In addition, undergraduate students will be taught on aspects of this project - either in final year undergraduate research projects or in summer research internships.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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