The causes and consequences of cell division asymmetries

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.