Size regulation in animal cells.

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A cell's size and physical dimensions are immediately apparent signatures of its identity. Size differences distinguish cell types, physiological conditions and pathologies. Despite this, the mechanisms that specify a cell's particular size remain unknown. The long term goal of this proposal is to understand how the particular size of animal cells is specified and regulated. Central to the regulation of cell growth is the protein complex mTORC1, a global regulator of cap dependent translation. Additionally, influence on cell growth has been established for Wnt, TGFb and the Hippo/Warts pathways. Despite the accumulated knowledge, a pertinent question remains: how do a common set of pathways specify different sizes in different cell types? In an earlier work we provided evidence for a cell-size discriminating process linking cell growth with the cell division cycle. Specifically, we showed that late in the G1 phase of cell cycle, growth becomes inversely dependent on cell size - larger cells accumulate less mass than smaller ones (Nature, 2013). The net result of this G1-specific process is a decrease in the cell-to-cell size variability. Cells become more similar in size, hence cell size becomes more finely specified. In follow-up, unpublished, investigations we identified evidence for two separate processes that effectively reduce cell size variability in proliferating populations. The first is a cell size checkpoint gating exit from the G1 phase of cell cycle. The second, and perhaps more interesting finding, is that on two separate times in cell cycle, the rate with which individual cells grow becomes inversely proportional to their size - larger cells increase their size slower than smaller cells. Last, we showed that the growth-rate regulation of cell size but not the G1-exit is regulated by mTORC1 and is inhibited by rapamycin. The specific goal of this proposal is to identify the molecular mechanism for these two separate size discriminatory processes. Our focus will center not on mechanisms of cellular enlargement but on how cellular enlargement is coordinated to result in a definite and specific cell size. Our question strikes at a fundamental unknown in cell biology: how do individual cells sense and monitor their size? To address these questions we take an interdisciplinary approach. We use mathematical techniques analogous to those used in statistical physics to answer biological questions from analysis of large-scale microscopy.