On being the right (cell) size Ginzberg, Miriam B.; Kafri, Ran; Krischner, Marc
Science,
05/2015, Letnik:
348, Številka:
6236
Journal Article
Recenzirano
Odprti dostop
How cells know when they are the right size
Biologists have long recognized that cells exist in a large range of sizes. Cell size is also flexible: Cells can differentiate into another cell type with ...a very different size. External factors can also influence cell size, but the consistent size of a given cell type shows that cells have mechanisms to measure their own size and adjust their growth rate or rate of cell division to maintain uniformity. Ginzberg
et al.
review recent advances in understanding how cells know when they are at the right size.
Science
, this issue
10.1126/science.1245075
BACKGROUND
How do the different cell types in our bodies maintain their distinctive and characteristic sizes? Although much is known about the signaling networks that stimulate or suppress cell growth, such as the mammalian target of rapamycin (mTOR) pathway, this central question remains: How do a common set of pathways precisely specify the appropriate size for any given cell type and physiological condition? The precision with which size is controlled is demonstrated by the uniformity in cell size typically seen in tissues. Most epithelial tissues, for example, display a striking regularity in the size and morphology of cells, whereas size heterogeneity can be a sign of neoplastic growth.
Most work on the subject of how cell size is regulated has explored the control of cell growth and proliferation by extracellular signals, such as growth factors and cytokines. However, although these signals can dictate the mean size of cells, individual cells will inevitably deviate from that mean. Variability in cell size can arise from variability in growth rate and cell-cycle length or asymmetry in cell division. These sources of variation raise the question of whether they are counteracted by cellular mechanisms that act to increase size homogeneity. Size variation can only be reduced with processes that differentially affect cells of different sizes, despite the fact that they share the same environment. This kind of control requires that individual cells measure their own size and adjust their behavior as necessary to achieve a common target size.
ADVANCES
In this Review, we present a growing body of evidence that suggests that animal cells autonomously measure and adjust their individual sizes to maintain uniformity within a population. We discuss possible mechanisms by which this can be achieved, including the size-dependent adjustment of cell-cycle length and/or growth rate, as well as the limitations of these strategies. We summarize the progress that has been made thus far in identifying the cell’s size control machinery and highlight important unanswered questions.
The presence of mechanisms ensuring precise size specification suggests that there may be an optimal cell size for a particular cell’s function. Here, we address the question of whether cells function most efficiently when at the “right” size by examining cases in which cell size was altered naturally or experimentally. Some tissues seem to easily compensate for cell-size changes, whereas in others, cells appear to perform best at their appropriate size. We highlight examples of cell types, such as pancreatic β cells and adipocytes, in which a relationship between cell size and cell function has been observed.
OUTLOOK
We conclude by discussing the gaps in our understanding of how cell size is regulated, stressing the questions that have been most neglected. Throughout this Review, we point out the experimental challenges that have hindered progress in this field and emphasize recent technological advances that may allow us to overcome these obstacles. Last, we pose the questions that we anticipate will guide this field in the upcoming years.
How is cell size specified?
(
Left
) In populations of proliferating cells, size uniformity may be ensured by linking the processes of growth and cell-cycle progression. One way this can be accomplished is by restricting progress through a particular cell-cycle stage (for example, the G
1
/S transition) to cells that have reached a specific “target” size. (
Right
) Typical sizes of various human cell types. Cells are drawn to scale: pancreatic β cells, hepatocytes, keratinocytes, fibroblasts, and adipocytes.
ILLUSTRATION CREDIT: K. SUTLIFF/
SCIENCE
Different animal cell types have distinctive and characteristic sizes. How a particular cell size is specified by differentiation programs and physiology remains one of the fundamental unknowns in cell biology. In this Review, we explore the evidence that individual cells autonomously sense and specify their own size. We discuss possible mechanisms by which size-sensing and size-specification may take place. Last, we explore the physiological implications of size control: Why is it important that particular cell types maintain a particular size? We develop these questions through examination of the current literature and pose the questions that we anticipate will guide this field in the upcoming years.
Biologists have long been concerned about what constrains variation in cell size, but progress in this field has been slow and stymied by experimental limitations. Here we describe a new method, ...ergodic rate analysis (ERA), that uses single-cell measurements of fixed steady-state populations to accurately infer the rates of molecular events, including rates of cell growth. ERA exploits the fact that the number of cells in a particular state is related to the average transit time through that state. With this method, it is possible to calculate full time trajectories of any feature that can be labelled in fixed cells, for example levels of phosphoproteins or total cellular mass. Using ERA we find evidence for a size-discriminatory process at the G1/S transition that acts to decrease cell-to-cell size variation.
While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for different cell types. ...It is increasingly clear that cell size is determined by size checkpoints—mechanisms that restrict the cell cycle progression of cells that are smaller than their target size. Previously, we described a p38 MAPK-dependent cell size checkpoint mechanism whereby p38 is selectively activated and prevents cell cycle progression in cells that are smaller than a given target size. In this study, we show that the specific target size required for inactivation of p38 and transition through the cell cycle is determined by CDK4 activity. Our data suggest a model whereby p38 and CDK4 cooperate analogously to the function of a thermostat: while p38 senses irregularities in size, CDK4 corresponds to the thermostat dial that sets the target size.
Display omitted
•Homeostatic mechanisms maintain cells at a given target size•p38 MAPK promotes growth of cells that are smaller than the critical target size•CDK4 determines the target size by regulating both the duration and rate of cell growth
Tan et al. study homeostatic mechanisms that maintain animal cells at their appropriate target size. They find that p38 is part of a sensing mechanism that identifies inappropriately sized cells, while CDK4 is analogous to a thermostat dial that sets the target size set point referenced by p38.
The spindle is a dynamic structure that changes its architecture and size in response to biochemical and physical cues. For example, a simple physical change, cell confinement, can trigger centrosome ...separation and increase spindle steady-state length at metaphase. How this occurs is not understood, and is the question we pose here. We find that metaphase and anaphase spindles elongate at the same rate when confined, suggesting that similar elongation forces can be generated independent of biochemical and spindle structural differences. Furthermore, this elongation does not require bipolar spindle architecture or dynamic microtubules. Rather, confinement increases numbers of astral microtubules laterally contacting the cortex, shifting contact geometry from "end-on" to "side-on." Astral microtubules engage cortically anchored motors along their length, as demonstrated by outward sliding and buckling after ablation-mediated release from the centrosome. We show that dynein is required for confinement-induced spindle elongation, and both chemical and physical centrosome removal demonstrate that astral microtubules are required for such spindle elongation and its maintenance. Together the data suggest that promoting lateral cortex-microtubule contacts increases dynein-mediated force generation and is sufficient to drive spindle elongation. More broadly, changes in microtubule-to-cortex contact geometry could offer a mechanism for translating changes in cell shape into dramatic intracellular remodeling.
Developmental processes in different mammals are thought to share fundamental cellular mechanisms. We report a dramatic increase in cell size during postnatal pancreas development in rodents, ...accounting for much of the increase in organ size after birth. Hypertrophy of pancreatic acinar cells involves both higher ploidy and increased biosynthesis per genome copy; is maximal adjacent to islets, suggesting endocrine to exocrine communication; and is partly driven by weaning-related processes. In contrast to the situation in rodents, pancreas cell size in humans remains stable postnatally, indicating organ growth by pure hyperplasia. Pancreatic acinar cell volume varies 9-fold among 24 mammalian species analyzed, and shows a striking inverse correlation with organismal lifespan. We hypothesize that cellular hypertrophy is a strategy for rapid postnatal tissue growth, entailing life-long detrimental effects.
Display omitted
•Mouse pancreatic acinar and beta cells grow dramatically during postnatal life•Acinar cell growth is a major contributor to postnatal pancreas growth in mice•Postnatal growth of the human pancreas relies entirely on increased cell number•Acinar cell size inversely correlates with lifespan among 24 mammalian species
Anzi et al. show that postnatal pancreas growth in mice relies to a large extent on cell growth, while human pancreas growth involves only increased cell numbers. Comparative analysis of 24 mammalian species revealed a striking negative correlation between pancreatic acinar cell size and organismal lifespan.
Cell biology. On being the right (cell) size Ginzberg, Miriam B; Kafri, Ran; Kirschner, Marc
Science (American Association for the Advancement of Science),
2015-May-15, 20150515, Letnik:
348, Številka:
6236
Journal Article
Recenzirano
Different animal cell types have distinctive and characteristic sizes. How a particular cell size is specified by differentiation programs and physiology remains one of the fundamental unknowns in ...cell biology. In this Review, we explore the evidence that individual cells autonomously sense and specify their own size. We discuss possible mechanisms by which size-sensing and size-specification may take place. Last, we explore the physiological implications of size control: Why is it important that particular cell types maintain a particular size? We develop these questions through examination of the current literature and pose the questions that we anticipate will guide this field in the upcoming years.
Biologists have long been concerned about what constrains variation in cell size; yet, progress on this question has been slow and stymied by experimental limitations
1
. We describe a new method, ...ergodic rate analysis (ERA), that uses single cell measurements of fixed steady-state populations to accurately infer the rates of molecular events, including rates of cell growth. ERA exploits the fact that the number of cells in a particular state is related to the average transit time through that state
2
. With this method, one can calculate full time trajectories of any feature that can be labeled fixed cells, for example levels of phospho-proteins or total cellular mass. Using ERA we find evidence for a size-discriminatory process at the G1/S transition that acts to decrease cell-to-cell size variation.
Abstract The study of genetic variance in opioid receptor antagonism of sucrose and other forms of sweet intake has been limited to reductions in sweet intake in mice that are opioid ...receptor-deficient or lacking either pre–pro-enkephalin or beta-endorphin. Marked genetic variance in inbred mouse strains has been observed for sucrose intake across a wide array of concentrations in terms of sensitivity, magnitude, percentages of kilocalories consumed as sucrose and compensatory chow intake. The present study examined potential genetic variance in systemic naltrexone's dose-dependent (0.01–5 mg/kg) and time-dependent (5–120 min) ability to decrease sucrose (10%) intake in eleven inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) mouse strains. A minimum criterion sucrose intake (1 ml) under vehicle treatment, designed to avoid “floor effects” of antagonist treatment was not achieved in three (A/J, AKR/J, CBA/J) inbred mouse strains. Marked genetic variance in naltrexone's ability to inhibit sucrose intake was observed in the remaining strains with the greatest sensitivity observed in the C57BL/10J and C57BL/6J strains, intermediate sensitivity in BALB/cJ, C3H/HeJ, CD-1 and DBA/2J mice, and the least sensitivity in 129P3/J, SWR/J and SJL/J strains with a 7.5–36.5 fold range of greater effects in the ID50 of naltrexone-induced inhibition in C57BL/10J relative to the three less-sensitive strains across the time course. Naltrexone primarily affected the maintenance, rather than the initiation of intake in BALB/cJ, CD-1, C3H/HeJ, DBA/2J and SJL/J mice, but significantly reduced sucrose intake at higher doses across the time course in C57BL/6J, C57BL/10J and 129P3/J mice. Whereas SWR/J mice failed to display any significant reduction in sucrose intake at any time point following any of the naltrexone doses, naltrexone's maximal magnitude of inhibitory effects was small (35–40%) in 129P3/J and SJL/J mice, moderate (∼ 50%) in BALB/cJ, C3H/HeJ, CD-1 and DBA2/J mice, and profound (70–80%) in C57BL/6J and C57BL/10J mice. Indeed, the latter two strains displayed significantly greater percentages of naltrexone-induced inhibition of sucrose intake than virtually all other strains. These data indicate the importance of genetic variability in opioid modulation of sucrose intake.
The feeding response following administration of the free fatty acid oxidation inhibitor, mercaptoacetate (MA) is conceptualized as an experimental model of lipoprivation, which may contribute to the ...understanding of inter-individual differences in the modulation of this homeostatic response. Although variation in the intake of food, water and glucoprivation as well as intake of several nutrients is known to be associated with genetic variation, it is not known whether MA-induced feeding is similarly dependent upon genotype. The present study therefore examined MA-induced feeding in mice of 11 inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL6/J, C57BL10/J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) strains across a wide range of previously determined effective MA doses (5, 35, 70, 100 mg/kg) and test times (1–4 h). MA produced significant dose-dependent and strain-dependent increases in food intake with strong responses noted in DBA/2J, outbred CD-1 and AKR/J mice. More limited dose-specific increases in food intake following MA occurred in C3H/HeJ, BALB/cJ, CBA/J, SJL/J, SWR/J and C57BL/6J mice. In contrast, MA failed to significantly increase food intake in A/J, C57BL/10J and 129P/3J mice. MA-induced food intake correlated significantly across strains only following the two highest doses, and intake following only the highest MA dose correlated significantly across strains with intake following only a moderate glucoprivic dose of 2-deoxy-
d-glucose. Thus, these inter-strain differences suggest that lipoprivic (e.g., MA intake) and glucoprivic (e.g., 2-deoxy-
d-glucose intake) responsivity operate via only partially overlapping genetic mechanisms of action. The demonstration of genotype-dependent variability in this lipoprivic response may provide the basis for the subsequent identification of trait-relevant genes.
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