Keeping up with the neighbours: developmental control of tissue growth through local cell communication

About the project

About the Project A 2027 Crick PhD project with Nic Tapon. Project background and description How do cells in a developing organism stop growing and dividing when the correct body size has been reached? How is tissue size maintained in an adult organism? These fundamental questions have clear implications for cancer, where cells lose the ability to respond to tissue size boundaries, and for regenerative medicine, where the proliferative potential of quiescent cells must be unleashed in a controlled manner. Our goal is to unravel how a diverse set of cues acting at the local, tissue autonomous level (e.g. mechanical forces, tissue architecture, signalling pathways) are integrated with systemic signals (e.g. nutrient availability, hormones) to determine final animal size. We tackle this question using Drosophila, mice, and cell in culture [1-3]. Over the past few years, we have established the Drosophila melanogaster abdominal epidermis as a system in which the fundamental principles of developmental growth can be elucidated using live-imaging, genetics and computational simulations [2]. Since the abdominal epidermis is a surface tissue and its growth occurs during the pupal stages when the animal is immobile, it is an ideal system to directly observe and rigorously quantify the patterns of developmental growth in a living organism. The abdominal epidermis develops from progenitor cells called histoblasts, which rapidly divide during pupal development to displace and kill the neighbouring larval epidermal cells (LECs). Once the histoblasts cover the entire abdominal surface, they undergo a rapid transition to cell cycle arrest and differentiate to give rise to the mature adult abdominal epidermis. Unpublished work from our lab has demonstrated that proliferating histoblasts coordinate their cell cycle progression. This coordination occurs locally through gap junctions, hexameric channels that allow exchange of small molecules between neighbouring epithelial cells. These findings open the exciting possibility that histoblasts exchange information that allows them to coordinate their exit from the cell cycle, ensuring accurate control of tissue size. Indeed, disruption of gap junctions is frequently associated with aberrant proliferation in cancer. In this project, we will explore the role of gap junctions in developmental growth control. First, we will use live-imaging and genetic/optogenetic tools to identify the key molecules that are transmitted through gap junctions to mediate cell cycle coupling. Candidates include calcium and nucleotides, which have recently been shown to be exchanged between epithelial cells and are essential for DNA replication [4]. We will then ask how mechanistically these molecules affect cell cycle progression and the transition to cell cycle arrest that determines final tissue size. Finally, we will elucidate the impact of this local cell cycle coupling on final tissue size and developmental robustness. Together, these approaches will shed light on how local cell communication enables tissue-wide coordination of complex processes like tissue growth. The student will be trained in a broad variety of cutting-edge techniques including genome engineering, optogenetics, live-imaging using confocal microscopy, and machine-learning-based image processing and analysis. This is just one example of the sort of project that might be available in this research group. The precise project will be decided on in consultation with the supervisor. Candidate background This project would suit a candidate with a degree and MRes/Msc in a biological discipline and a passion for developmental biology. Skills in quantitative biology and computational approaches to biological data would be a plus. Lab-specific question Identify a finding, technique or approach from your previous research that you think could be relevant to our work. How might you apply or develop this in a PhD project in our lab?

Research areas