Exploring Coordination of Cell Cycle Regulation as a Mechanism for Collective Cell Growth in the D. melanogaster Germline

Abstract

Collective cell growth has been observed across many life forms and across all stages of development, and it is necessary for life. Thus, it is of great interest to characterize the coordinated regulation of collective cell growth and ultimately to control this behavior to achieve desirable outcomes. The phenomenon of collective cell growth, however, is poorly understood due to the complexity of large cell populations; therefore, it is desirable to study a small, well-understood network of uniquely identifi able cells in which collective growth can be characterized. In Drosophila melanogaster, the coordinated regulation of cell growth is necessary for the formation and development of the egg chamber that ultimately gives rise to the egg. This small multicellular system offers a powerful platform for understanding the phenomenon of coordinated growth of cells in a population, and the wealth of knowledge that exists in the field of D. melanogaster development provides a strong foundation to further investigate this phenomenon. Our work aimed to explore the mechanism of coordinated cell growth using the D. melanogaster egg chamber, a small-cell network where coordination of cell growth is evident in the emergence of size coordination groups among the germline nurse cells of the egg chamber. To investigate this phenomenon, our work focused on the coordination of cell cycle regulation as a mechanism for the emergence of these size coordination groups, via a modi fied cell cycle known as the endocycle. By implementing a cross-sectional study, we were able to extract the nuclear localization dynamics of key endocycle regulators Cyclin E and Dacapo. We found that nuclear localization patterns of these proteins appear to be highly correlated among nurse cells of the same coordination group. Furthermore, for both proteins, our work suggests the presence of out-of-phase oscillations in the concentrations of the same protein among nurse cells of adjacent coordination groups. To investigate how this behavior may arise in light of our frequency analysis, which suggests that nurse cells endocycle at the same frequency, we created a basic mathematical model of coupled limit cycle oscillators in the nurse cell network. Our model suggests that the topology of the nurse cell net- work, strong oocyte-biased diffusive transport in the network, and a long timescale of diffusion are capable of creating the conditions necessary for the emergence of size coordination groups, but that other mechanisms may be responsible for creating the size hierarchy observed experimentally. Our work establishes the coordination of cell cycle regulation as a possible mechanism for coordination of cell growth in cell populations and provides a basis upon which future studies may find signifi cance.