Mechanisms Controlling Cell Size in Animal Cells

Although questions on cell size have been investigated for more than half a century, molecular mechanisms that ‘program’ the size of animal cells are only starting to be revealed. My Ph.D. research focuses on the molecular mechanisms that promote cell size uniformity in proliferating mammalian cells. By relying on a high-content small chemical screen, I identified candidate proteins and signaling molecules that may function as cell size specifiers. Intriguingly, analysis of the screen hits suggested a role for the p38 MAPK in the long-sought mammalian cell size checkpoint. In follow-up experiments, I showed that p38 MAPK signaling is activated in small, but not large cells, which selectively inhibits the progression of small cells into S phase. Consistent with this model, chemical and genetic perturbations of p38 resulted in the loss of the compensatory G1 length extension in small cells; cells lacking p38 activity proliferated faster, were smaller in size and displayed increased size heterogeneity. Altogether, my work suggests that the p38 MAPK pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity. In this thesis, I first present an in-depth review of the animal cell size research. Reflecting on literature, I summarize in Chapter 1.1 a convergence of historical and recent evidence that support size sensing as a cell-autonomous function of individual animal cells. I also discuss the historical debates on animal cell size sensing and offer my understanding of how these “conflicting” literature may be resolved through new interpretations. In Chapter 1.2, I discuss in detail how cell size affects cellular, tissue and organismal level functions. I hope this inspires more functional and mechanistic research on cell size in the future. In the last Chapter, I further discuss the implications of the p38 signaling and cell size control and introduce in brief the branches of follow-up research that emerged from my thesis work.Ph.D