Award details

The causes and consequences of cell division asymmetries

Reference	BB/R009732/1
Principal Investigator / Supervisor	Professor Buzz Baum
Co-Investigators / Co-Supervisors
Institution	University College London
Department	Lab for Molecular Cell Bio MRC-UCL
Funding type	Research
Value (£)	432,396
Status	Completed
Type	Research Grant
Start date	01/02/2018
End date	31/07/2021
Duration	42 months

Abstract

This project aims to study the causes and consequences of asymmetries that occur during cell division in mammalian cell culture and in cells of the developing fly bristle lineage. To begin, we will quantify the variation in size (mass and volume) of sibling cells by following symmetrical mammalian cell divisions in culture. We will then use a perturbation analysis to define the roles of the following processes in the regulation of differences in sibling birth size: i) spindle positioning ii) polar relaxation iii) furrow ingression and slippage iv) cytoplasmic flow in the intercellular bridge prior to abscission. Using the knowledge gained from this analysis, we will then study how these factors are adapted in natural occurring asymmetric cell divisions in the Drosophila bristle lineage (using symmetric epithelial divisions as a control). This is an ideal system by which to study the source and function of division asymmetries, since the four cells of the mechanosensory organ arise from a series of four divisions that are asymmetric in size as well as in fate. Although asymmetries in the inheritance of cell fate regulators have been well-studied in this system, little is known about the variation, mechanisms and functions of the asymmetries in cell size that accompany each division in the lineage. Our focus will be on the generation of asymmetries in apical surface area, since it is at this level that cells first wrap around one another. In this work we will quantify the natural variation in division symmetry, identify common sources of these errors and the conserved mechanisms used to correct them, and will assess the function of division asymmetries in cell size and apical cell area during the formation of a complex organ. Through addressing this fundamental but poorly understood problem in biology, we think this work will have impact in a wide range of fields from stem cell biology to cancer cell biology.

Summary

While manufactured objects tend to be built by putting together different parts of fixed size, like lego bricks, living systems are constructed by cell growth and division. In fact, all the cells in a multicellular animal, like a human or fly, are derived in this way from a single fertilised egg cell. How then do organisms generate the cell type diversity required to build complex organs and tissues? This is achieved in part from cell divisions that are asymmetric - as single cells divide to generate siblings that take up different fates as the result of asymmetries in their inheritance or in their environment. While the asymmetric segregation of molecules that help to determine differences in sibling cell fate have been studied in detail, many of these divisions are also characterised by reproducible differences in sibling cell size and shape. How and why this is the case is not understood. To shed light on this, here we aim to study the regulation and function of the differences in cell mass, volume and surface area that arise from asymmetries in the division process. Although the importance of the size and shape of an animal cell for its behavior and function has been recognised for at least 100 years, since D'Arcy Thompson, little work has been done to quantify the variation in sibling cell size and shape, to define the mechanisms that underlie division errors, nor their contribution to cell behavior and function. Nevertheless, the fact that reproducible differences in sibling cell size and shape are frequently associated with asymmetric stem cell divisions, suggests that they are likely to be important. This is probably more significant in the context of organ development, where cells with different fates must work together as a functional unit. A good example of this is the developing fly bristle, where four cells generated via a series of asymmetric divisions form a complex three dimensional structure that functions in mechanosensation. Here, taking advantage of recent advances in imaging, we aim to use two complementary model systems, mammalian cells in culture and cells of the fly bristle lineage to determine: i) sources of error that affect the distribution of cell mass and volume at division during both symmetric and asymmetric divisions, ii) the points at which errors in division symmetry are corrected in both cases (differences between cells mustn't be eliminated during asymmetric divisions), and iii) the functions of asymmetries in the size and shape of sibling cells in the context of organogenesis. Moreover, in the case of the bristle, where cells must wrap around one another in order to form a functional organ, we will explore the extent to which differences in the volume and apical surface area of individual cells generated by asymmetries in division are corrected or amplified. Overall, we expect our analysis to have an important impact on our understanding of conserved elements of the division process that determine its accuracy, and to shed light on the function of size and shape differences between sibling cells in the context of organogenesis. We also expect this work to have implications for our understanding of stem cell divisions in humans, many of which are thought to be asymmetric, and for cancer research since cancer cells frequently exhibit a profound loss of cell size homeostasis.

Impact Summary

As a consequence of the discoveries made during the course of this proposed study, we expect this work to have impact on related areas of research done within the scientific community at UCL, in the UK and beyond, particularly in the field of cell and developmental biology, stem cell biology and cancer biology. We also expect this work to have a longterm benefit to the health and wealth of the UK. While fundamental, we expect our work to have implications for our understanding of human stem cell biology and cancer biology. It is hoped that in the longterm this may lead to developments in regenerative medicine and in cancer therapy. In addition, we expect this work to have impact in the wider public - with whom we expect to interact during open days, school visits and through the media. More specifically, the work will highlight the importance of using simple model systems like the fly to address fundamental problems that are relevant to human health and wellbeing. Through this work, we expect to establish and strengthen our existing collaborations with experts in field of cell biology both nationally and internationally. Training: This work will provide a platform for training Nitya Ramkumar as she progresses towards becoming an independent group leader. She has helped to develop this line of research, and has driven the project over the last two years. In the coming years I expect her to be able to use the work done as part of this project as a platform upon which to launch her career. During the course of the project we also expect to train a number of Undergraduates, Masters level and PhD students. Through this work they will learn new methods. Most importantly, they will learn the challenges and excitement of exploring new areas of biology, using intelligence, passion, imagination, rigour and integrity. This will also provide Nitya Ramkumar with experience in mentoring under Buzz Baum's guidance. Finally, to ensure maximum impact we will present this work at national and international meetings covering topics related to cell division, cell size regulation, Drosophila genetics, developmental biology, cell biology like British Society for Cell Biology and American Society for Cell Biology. We will publish the main biological findings in high impact journals. Additionally, tools developed during this project will be made available to the community, subject to patent filing. Published fly stocks developed during the course of this work will be given to Bloomington to distribute.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
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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