Probing the flexibility of G0

Project Summary/Abstract The cell cycle is an ordered series of molecular events in a cell leading to division and production of two daughter cells. This process is fundamental to the development of all multicellular organisms, which begin from a single cell, the fertilized egg. Equally important for proper development though, is the slowing or stopping of the cell cycle at the right places and times as cells, tissues and organs mature. In fact, the majority of cells in multicellular organisms spend most of their existence in non-proliferating states, often referred to as cellular quiescence or the G0 phase. In their non-dividing state, quiescent cells are metabolically active and carry out critical physiological functions in tissues and organs. Despite the importance of G0, most studies of cell cycle regulation have focused on rapidly dividing cells. Thus, it remains unclear how cells choose to enter G0 during development, and why some cells can choose to leave G0 and later re-enter the cell cycle in response to developmental signals, tissue damage, or nutrient availability while others cannot. It has become clear that there are multiple states of G0, some that are readily reversible, and others that are permanent. Different states of states may be controlled in distinct ways, both in the manner of cell cycle inhibition and in the pathways used to initiate exit. The goal of the work described here is to understand how the cell cycle machinery is controlled during the decision to exit the cell cycle, and how G0 can be modulated to be more or less reversible in different contexts. This work impacts a wide range of biological questions, as the proper control of quiescence is critical in development and tissue regeneration, but becomes disrupted in aging and cancer.