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Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity.

ABSTRACT: Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity. This regulation was also observed directly by monitoring nuclear growth in live cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical/genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size. Additionally, although Rb signaling is not required for these regulatory behaviors, perturbing Cdk4 activity still influences cell size, suggesting that the Cdk4 pathway may play a role in designating the cell's target size.

SUBMITTER: Ginzberg MB

PROVIDER: S-EPMC6031432 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity.

Ginzberg Miriam Bracha MB Chang Nancy N D'Souza Heather H Patel Nish N Kafri Ran R Kirschner Marc W MW

eLife 20180611

Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity. This regulation was also observed directly by monitoring nuclear growth in live ...[more]

PMID: 29889021

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Project description:Quorum sensing (QS) is a microbial cell-cell communication system that regulates gene expression in response to population density to coordinate collective behaviors. Yet, the role of QS in resolving the stresses caused by the accumulation of toxic metabolic by-products at high cell density is not well defined. In response to cell density, QS could be involved in reprogramming of the metabolic network to maintain population stability. Using unbiased metabolomics, we discovered that Vibrio cholerae mutants genetically locked in a low cell density (LCD) QS state are unable to alter the pyruvate flux to convert fermentable carbon sources into neutral acetoin and 2,3-butanediol molecules to offset organic acid production. As a consequence, LCD-locked QS mutants rapidly lose viability when grown with fermentable carbon sources. This key metabolic switch relies on the QS-regulated small RNAs Qrr1-4 but is independent of known QS regulators AphA and HapR. Qrr1-4 dictate pyruvate flux by translational repression of the enzyme AlsS, which carries out the first step in acetoin and 2,3-butanediol biosynthesis. Consistent with the idea that QS facilitates the expression of a common trait in the population, AlsS needs to be expressed cooperatively in a group of cells. Heterogeneous populations with high percentages of cells not expressing AlsS are unstable. All of the cells, regardless of their respective QS states, succumb to stresses caused by toxic by-product accumulation. Our results indicate that the ability of the bacteria to cooperatively control metabolic flux through QS is critical in maintaining a sustainable environment and overall population stability.ImportanceOur work reveals a novel role for Vibrio cholerae quorum sensing (QS) in relieving the stresses caused by toxic metabolite accumulation when the population becomes crowded through metabolic reprogramming. QS enables V. cholerae switching from a low cell density energy-generating metabolism that is beneficial to individuals at the expense of the environment to a high cell density mode that preserves environmental habitability by sacrificing individual fitness. This cooperative switch provides a stable environment as the common good in maintaining the stability of the community. However, the common good can be exploited by uncooperative mutants that pollute the environment, causing population collapse. Our findings provide insights into the metabolic stress response of a major human pathogen, with implications for our understanding of microbial social biology and cooperation from an ecological and evolutionary perspective.

Project description:Apicomplexan parasites can change fundamental features of cell division during their life cycles, suspending cytokinesis when needed and changing proliferative scale in different hosts and tissues. The structural and molecular basis for this remarkable cell cycle flexibility is not fully understood, although the centrosome serves a key role in determining when and how much replication will occur. Here we describe the discovery of multiple replicating core complexes with distinct protein composition and function in the centrosome of Toxoplasma gondii. An outer core complex distal from the nucleus contains the TgCentrin1/TgSfi1 protein pair, along with the cartwheel protein TgSas-6 and a novel Aurora-related kinase, while an inner core closely aligned with the unique spindle pole (centrocone) holds distant orthologs of the CEP250/C-Nap protein family. This outer/inner spatial relationship of centrosome cores is maintained throughout the cell cycle. When in metaphase, the duplicated cores align to opposite sides of the kinetochores in a linear array. As parasites transition into S phase, the cores sequentially duplicate, outer core first and inner core second, ensuring that each daughter parasite inherits one copy of each type of centrosome core. A key serine/threonine kinase distantly related to the MAPK family is localized to the centrosome, where it restricts core duplication to once per cycle and ensures the proper formation of new daughter parasites. Genetic analysis of the outer core in a temperature-sensitive mutant demonstrated this core functions primarily in cytokinesis. An inhibition of ts-TgSfi1 function at high temperature caused the loss of outer cores and a severe block to budding, while at the same time the inner core amplified along with the unique spindle pole, indicating the inner core and spindle pole are independent and co-regulated. The discovery of a novel bipartite organization in the parasite centrosome that segregates the functions of karyokinesis and cytokinesis provides an explanation for how cell cycle flexibility is achieved in apicomplexan life cycles.

Dataset Information

Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity.

Publications

Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity.

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