Size control goes global

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The size of cells, tissues and organisms is a fundamental yet poorly understood attribute of biological systems. Traditional difficulties in interrogating the basis for size regulation have been surmounted by recent systematic phenotypic analyses. Genome-wide size screens in yeast suggest that ribosome biogenesis rate dictates cell size thresholds, whereas analogous RNAi-based size screens in metazoans cells reveal further connections between cell size and translation, as well as myriad other pathways. Sophisticated genetic screens in flies have delineated the new Hippo-signalling pathway that controls tissue and organ size. While the plethora of genes that alter size phenotypes at present defies a unified model, systems-level analysis suggests many new inroads into the longstanding enigma of size control.

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Size: a system level attribute

The size of organisms on this planet ranges over an enormous scale, from recently described nano-organisms that have an estimated cell volume of a mere 6 aL [1] to giant Armillaria fungi that can literally span thousands of acres [2]. Even within an organism, the size of cells varies remarkably, for example from metre long motorneurons to mature lymphocytes that are 100 000 times smaller. Despite the importance of size in biology, JBS Haldane penned in his famous essay, On Being the Right Size

The balance between growth and division

Gross changes in body size are wrought through developmental control of tissue and organ size thresholds, as effected by master hormonal regulators [3••]. Intriguingly, some mutations that perturb cell size also alter organ size, whereas others do not, suggesting a fractious relationship between the various size thresholds [4]. The most conserved and, to this point, most mysterious correlate of cell size is genome ploidy: In any given species, cell size scales with cell ploidy in a remarkably

Yeast rises to the size challenge again

Before the molecular genetic era, the study of cell size homeostasis was at the vanguard of cellular physiology in fission and budding yeast [6, 11], as well as in cultured mammalian cells [7]. The isolation of the small cell size mutant wee1 in fission yeast and its identification as a Cdc2 regulatory kinase proved crucial in establishing the basis of G2/M cell cycle regulation; similarly, isolation of the budding yeast small cell size mutant WHI1-1 and its identification as the first yeast G1

Metazoan cell size control: genome-scale analysis takes flight

Construction of a collection of dsRNA targeting all predicted open reading frames (ORFs) in Drosophila (www.flyrnai.org), and associated methodology to transfect cultured cells in high-throughput fashion has enabled analogous systematic screens for Drosophila genes involved in cell growth and division. The first such screen not only focused on morphological readouts, but also identified cell size regulators [42]. Determination of cell size and cell cycle phenotypes of all predicted protein

The next frontier: organ size control

In contrast to autonomous effects of many genes on the size of single cells, the larger puzzle of how organ size is set has yet to be placed in a systematic framework [50]. Despite the host of genes that affect cell size in S2 cells, very few have a significant influence on organ size. For example, when cell division in a compartment of the developing Drosophila wing is accelerated by overexpression of the G1/S transcription factor E2F, the increase in cell number is precisely compensated by a

The big picture: determinants of organism size

Genome-scale screens for modulators of whole organism size seem set to add a final layer on the underlying labyrinth of cell and organ size control networks. The control of body size in metazoans is under complex hormonal and nutrient control mechanisms that appear to vary widely even between related species [3••]. C. elegans is a particularly interesting model in this regard as each cell in the adult is the product of a fully determined lineage, unlike the more plastic developmental programme

Conclusion: sizing up future prospects

As systems biology approaches mature, previously intractable systems-level problems such as size control will inexorably begin to yield. As size control networks are mapped, further relationships between size, division, survival, tissue structure and myriad signalling pathways will emerge. These linkages will in turn illuminate the central role of growth processes in disease, notably cancer. Given the pleiotropic nature of size control, the elaboration of size control mechanisms in other model

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize that many important contributions to the size control field could not be cited because of space constraints. We thank Helen McNeill, Anne-Claude Gingras, Eric Weiss, Laurence Pelletier, Lorrie Boucher, Jeff Sharom, Brandt Schneider, Bruce Futcher and Paul Jorgensen for stimulating discussions on size control and genome-wide screens. Research in the Tyers laboratory is supported by grants from the Canadian Institutes of Health Research (CIHR) and the National Cancer Institute of

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