Dilution of the cell cycle inhibitor Whi5 controls budding-yeast cell size

Schmoller, Kurt M.; Turner, Jonathan J.; Kõivomägi, Mardo; Skotheim, Jan M.

doi:10.1038/nature14908

Cited by 301 publications

(580 citation statements)

References 37 publications

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“…Thus, cell size is proportional to growth rate, which means that slow growing cells can be nearly half the size of rapidly growing cells (Johnston et al 1977;Fantes and Nurse 1977). Conversely, at least in some cases cell size influences growth rate so that large cells grow faster than small cells (Tzur et al 2009;Sung et al 2013;Schmoller et al 2015;Leitao and Kellogg 2017). Together, these observations show that growth rate is matched to nutrient availability, cell size is matched to growth rate, and growth rate is matched to cell size.…”

Section: Introductionmentioning

confidence: 54%

Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast

et al. 2018

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Nutrient availability, growth rate and cell size are closely linked. For example, in budding yeast, the rate of cell growth is proportional to nutrient availability, cell size is proportional to growth rate, and growth rate is proportional to cell size. Thus, cells grow slowly in poor nutrients and are nearly half the size of cells growing in rich nutrients. Moreover, large cells grow faster than small cells. A signaling network that surrounds Tor kinase complex 2 (TORC2) plays an important role in enforcing these proportional relationships. Cells that lack components of the TORC2 network fail to modulate their growth rate or size in response to changes in nutrient availability. Here, we show that budding yeast homologs of the Lkb1 tumor suppressor kinase are required for normal modulation of TORC2 signaling in response to changes in carbon source. Lkb1 kinases activate Snf1/AMPK to initiate transcription of genes required for utilization of poor carbon sources. However, Lkb1 influences TORC2 signaling via a novel pathway that is independent of Snf1/AMPK. Of the three Lkb1 homologs in budding yeast, Elm1 plays the most important role in modulating TORC2. Elm1 activates a pair of related kinases called Gin4 and Hsl1. Previous work found that loss of Gin4 and Hsl1 causes cells to undergo unrestrained growth during a prolonged mitotic arrest, which suggests that they play a role in linking cell cycle progression to cell growth. We found that Gin4 and Hsl1 also control the TORC2 network. In addition, Gin4 and Hsl1 are themselves influenced by signals from the TORC2 network, consistent with previous work showing that the TORC2 network constitutes a feedback loop. Together, the data suggest a model in which the TORC2 network sets growth rate in response to carbon source, while also relaying signals via Gin4 and Hsl1 that set the critical amount of growth required for cell cycle progression. This kind of close linkage between control of cell growth and size would suggest a simple mechanistic explanation for the proportional relationship between cell size and growth rate.3

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Section: Introductionmentioning

confidence: 54%

Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast

et al. 2018

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“…Bck2) should be tested to ascertain their relative effects on dependence between mass at budding and duration of S/G 2 /M. Recent experimental work in budding yeast suggests an intriguing mechanistic model for size control in which dilution of Whi5 as the cell grows in volume dictates cell cycle entry near the G 1 /S transition [5]. Our work could be extended to analyse changes in concentration of Whi5 and other proteins during S/G 2 /M to identify potential mechanistic bases for the dependencies we observe.…”

Section: Resultsmentioning

confidence: 99%

“…In the budding yeast Saccharomyces cerevisiae, cell division is known to be coordinated with cell growth [1][2][3][4][5][6] (reviewed in [7]). This dependence between growth and division is most noticeable in daughter cells that, owing to the asymmetric manner of budding yeast division, are born smaller than their mothers (figure 1).…”

Section: Introductionmentioning

confidence: 99%

Characterization of dependencies between growth and division in budding yeast

Mayhew

Iversen

Hartemink

2017

J. R. Soc. Interface.

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Cell growth and division are processes vital to the proliferation and development of life. Coordination between these two processes has been recognized for decades in a variety of organisms. In the budding yeast Saccharomyces cerevisiae, this coordination or 'size control' appears as an inverse correlation between cell size and the rate of cell-cycle progression, routinely observed in G 1 prior to cell division commitment. Beyond this point, cells are presumed to complete S/G 2 /M at similar rates and in a size-independent manner. As such, studies of dependence between growth and division have focused on G 1 . Moreover, in unicellular organisms, coordination between growth and division has commonly been analysed within the cycle of a single cell without accounting for correlations in growth and division characteristics between cycles of related cells. In a comprehensive analysis of three published time-lapse microscopy datasets, we analyse both intra-and inter-cycle dependencies between growth and division, revisiting assumptions about the coordination between these two processes. Interestingly, we find evidence (i) that S/G 2 /M durations are systematically longer in daughters than in mothers, (ii) of dependencies between S/G 2 /M and size at budding that echo the classical G 1 dependencies, and (iii) in contrast with recent bacterial studies, of negative dependencies between size at birth and size accumulated during the cell cycle. In addition, we develop a novel hierarchical model to uncover inter-cycle dependencies, and we find evidence for such dependencies in cells growing in sugar-poor environments. Our analysis highlights the need for experimentalists and modellers to account for new sources of cell-to-cell variation in growth and division, and our model provides a formal statistical framework for the continued study of dependencies between biological processes.

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“…In the SAM, our data show that cell surface area and volume are regulated by a mode intermediate between critical size and critical increment. In budding yeast daughter cells, through cyclin-dependent kinase (CDK)/cyclin activity inhibition, the transcriptional inhibitor Whi5 controls cell size at G1/S via a dilution process whereby Whi5 is synthesized at a roughly constant rate through S/G2/M, which lasts for an approximately fixed time, and is then diluted out by growth during G1, triggering S-phase when it falls below a specific concentration (49). This or a similar mechanism can potentially implement the critical increment mode of size regulation (8).…”

Section: Discussionmentioning

confidence: 99%

Cell size and growth regulation in the Arabidopsis thaliana apical stem cell niche

Willis

Refahi

Wightman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

180

217

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Cell size and growth kinetics are fundamental cellular properties with important physiological implications. Classical studies on yeast, and recently on bacteria, have identified rules for cell size regulation in single cells, but in the more complex environment of multicellular tissues, data have been lacking. In this study, to characterize cell size and growth regulation in a multicellular context, we developed a 4D imaging pipeline and applied it to track and quantify epidermal cells over 3-4 d in Arabidopsis thaliana shoot apical meristems. We found that a cell size checkpoint is not the trigger for G2/M or cytokinesis, refuting the unexamined assumption that meristematic cells trigger cell cycle phases upon reaching a critical size. Our data also rule out models in which cells undergo G2/M at a fixed time after birth, or by adding a critical size increment between G2/M transitions. Rather, cell size regulation was intermediate between the critical size and critical increment paradigms, meaning that cell size fluctuations decay by ∼75% in one generation compared with 100% (critical size) and 50% (critical increment). Notably, this behavior was independent of local cell-cell contact topologies and of position within the tissue. Cells grew exponentially throughout the first >80% of the cell cycle, but following an asymmetrical division, the small daughter grew at a faster exponential rate than the large daughter, an observation that potentially challenges present models of growth regulation. These growth and division behaviors place strong constraints on quantitative mechanistic descriptions of the cell cycle and growth control.cell size | cell growth | cell cycle | homeostasis | plant stem cells H ow cells coordinate growth and division to achieve a particular cell size remains a fundamental question in biology. Our understanding of this basic property of cells is limited, in part, by the lack of quantitative data on cellular growth and size kinetics over multiple generations, especially in higher eukaryotes (1). Classical studies of cell size homeostasis focused on whether division occurred upon reaching a critical size or after a fixed time period has elapsed (2, 3). However, time-lapse studies of single-celled organisms spanning a range of bacteria (4-7) and the yeast Saccharomyces cerevisiae (8) have recently indicated that cell size is regulated by the addition of a fixed volume increment between divisions. Identification of the size regulation behavior constrains the set of feasible molecular scenarios for how growth and division are coordinated with the cell cycle (8-10). In multicellular tissues, the loss of growth and division/cell cycle coordination could have an impact on the organism's development, yet, to the best of our knowledge, cell growth and size kinetics have never before been measured over generations in a tissue context. The experimental challenges are particularly acute because interdivision times are often on the order of tens of hours, cells have a diversity of shapes necessitating di...

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Dilution of the cell cycle inhibitor Whi5 controls budding-yeast cell size

Cited by 301 publications

References 37 publications

Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast

Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast

Characterization of dependencies between growth and division in budding yeast

Cell size and growth regulation in the Arabidopsis thaliana apical stem cell niche

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