Metazoans precisely control the number of cell divisions to maintain homeostasis during organ or tissue development throughout their lifetime. In adult metazoans, most differentiated cells have completed proliferation and lie in a quiescent state, also termed cell cycle exit. The decision to proliferate or enter quiescence is essential during development and its dysregulation may lead to defects in organogenesis, wounding healing and regeneration as well as tumor formation. However, at what stage of the cell cycle the decision occurs and what molecular mechanisms control this decision remain controversial.
In my thesis work, I have revealed a novel role for Protein Phosphatase 2A (PP2A) complex in promoting the transition to quiescence during tissue development in vivo. Using Drosophila eyes and wings as a model, I found that compromising PP2A activity during the final cell cycle prior to a developmentally controlled cell cycle exit leads to extra cell divisions and delayed entry into quiescence. By systematically testing the regulatory subunits of Drosophila PP2A, I discovered that the B56 family member widerborst (wdb) is required for the role of PP2A in promoting the transition to quiescence. In particular, PP2A/B56 complex targets cyclin-dependent kinase 2 several hours after mitosis to promote cells entry into quiescence, indicating when the decision occurs and how PP2A impacts the decision.
In the other half of my thesis work, I investigated the dynamic features of the proliferation-quiescence transition with the application of a novel fluorescent cell cycle reporter and time-lapse, live-cell imaging in a mammalian cell population. By monitoring the proliferation-quiescence transition, I discovered that the quiescent state is quite heterogeneous. I found that mammalian cells can enter into either a transient or long quiescent state after mitosis, prior to the next round of cell cycle even under conditions of abundant nutrients. Notably, I discovered that two sister cells born of the same mitosis often make heterogeneous cell cycle decisions, with one cell entering long-term quiescence while the other re-enters the cell cycle for the next round of division. Consistent with my work in Drosophila model, PP2A in mammals plays a conserved role in promoting the entry into quiescence. This novel role of PP2A in modulation of the proliferation-quiescence decision may contribute to its long-known tumor suppressor role and impact the emerging problem of tumor dormancy.