Cell volume and surface area are conserved during cell division
the verdict
CONTESTED
contested - the weight sits with the supporting side
refutedsupported
the weight of evidence
4 sources for · 0 against
The retrieved sources discuss cellular morphology regulation and mitochondrial growth and division during the cell cycle, but provide only partial and context-dependent evidence rather than full support for the strict conservation of overall cell volume and surface area during division.
The steady-state size of bacterial cells correlates with nutrient-determined growth rate. Here, we explore how rod-shaped bacterial cells regulate their morphology during rapid environmental changes. We quantify cellular dimensions throughout passage cycles of stationary-phase cells diluted into fresh medium and grown back to saturation. We find that cells exhibit characteristic dynamics in surface area to volume ratio (SA/V), which are conserved across genetic and chemical perturbations as well as across species and growth temperatures. A mathematical model with a single fitting parameter (the time delay between surface and volume synthesis) is quantitatively consistent with our SA/V experimental observations. The model supports that this time delay is due to differential expression of volume and surface-related genes, and that the first division after dilution occurs at a tightly controlled SA/V. Our minimal model thus provides insight into the connections between bacterial growth rate and cell shape in dynamic environments. Bacterial cells actively change their size and shape in response to external environments. Here, Shi et al. explore how cells regulate their morphology during rapid environmental changes, showing that the characteristic dynamics of surface area-to-volume ratio are conserved across genetic and chemical perturbations, as well as across species and growth temperatures.
We find that cells exhibit characteristic dynamics in surface area to volume ratio (SA/V), which are conserved across genetic and chemical perturbations as well as across species and growth temperatures. A mathematical model with a single fitting parameter (the time delay between surface and volume synthesis) is quantitatively consistent with our SA/V experimental observations. The model supports that this time delay is due to differential expression of volume and surface-related genes, and that the first division after dilution occurs at a tightly controlled SA/V.
Our minimal model thus provides insight into the connections between bacterial growth rate and cell shape in dynamic environments. Subject terms: Cell growth, Bacteria, Bacteriology, Cellular microbiology Bacterial cells actively change their size and shape in response to external environments. Here, Shi et al. explore how cells regulate their morphology during rapid environmental changes, showing that the characteristic dynamics of surface area-to-volume ratio are conserved across genetic and chemical perturbations, as well as across species and growth temperatures.
In a previous study, it was shown that the regulation of surface area to volume ratio (SA/V) is such a process upstream of cell width and length determination: switching cells at steady state to a condition in which only cell wall (i.e., surface area) synthesis is partially inhibited increased both cell width and length, which lowers SA/V 23 .
Therefore, cells did not divide at a critical cell width, nor did they widen by a fixed amount before division (Supplementary Fig. 2a ), suggesting that cell width changes do not directly trigger the first division during stationary-phase outgrowth. Cell volume at division negatively correlated with the initial volume (Fig. 3d ), indicating that the first division exiting stationary phase is not triggered by a critical volume or a critical added volume. Similar negative correlations were observed for surface area, cell length, and cross-sectional area (Supplementary Fig. 2b–d ). Time to first division (Fig. 3e ) and instantaneous growth rate at division (Supplementary Fig.
2e ) both negatively correlated with initial cell volume, indicating that division does not occur after a fixed time interval or when cells reach a critical growth rate. Previous work suggested that exponentially growing cells accumulate excess surface area material during the cell cycle, which then triggers division 23 . For a rod-shaped cell, division adds two hemispheric poles and increases SA by 4% without changing volume (Supplementary Fig. 2f ). Since cells decrease their SA/V during outgrowth (Fig. 1d ), we thus asked whether the first division after cells exit from stationary phase was also related to their SA/V.
Similar changes in width have been reported in growth-inhibited cells due to the presence of an antibiotic, in which E. coli cells resumed growth after washing out the antibiotic and cell width increased prior to length increase 42 . The initial widening of cells is likely related to active growth, in which the transcriptional program favors synthesis of cytoplasmic proteins over envelope-related proteins (Fig. 2d, e ), resulting in the subsequent imbalance between surface area and
Regardless, our findings strongly suggest that the dynamic coordination between surface area and volume growth dictates cell shape. E. coli cell division at steady state is well described by the adder model 44 . However, for cells growing out of stationary phase, we observed that cells did not add a constant volume, surface area, width, or length (Fig. 3d , Supplementary Fig. 2a–d ). A recent study suggested that E. coli cells exhibit “sizer” behavior when exiting from stationary phase (first division at a critical size) 45 . While our data also showed near-“sizer” behavior (Fig. 3d , Supplementary Fig. 2b–d ), we found that a critical SA/V was more likely to dictate the first division (Fig.
3h, i , Supplementary Fig. 2h ), consistent with previous work showing that a threshold of FtsZ is required for cell division 46 , 47 . The dynamics of FtsZ were further delayed compared to other cell-wall synthesis genes (Fig. 2e , Supplementary Fig. 2h ), reinforcing the idea that gene expression during growth resumption is temporally regulated to allow cells to prioritize volumetric growth over surface area synthesis or division. Our model of SA/V dynamics links cell width and length, even though the two dimensions are regulated by distinct molecular machineries 15 , 16 , 36 .
Bacterial cells constantly face complex environmental changes in their natural habitats. While steady-state cell size correlates with nutrient-determined growth rate, it remains unclear how cells regulate their morphology during rapid environmental changes. Here, we systematically quantified cellular dimensions throughout passage cycles of stationary-phase cells diluted into fresh medium and grown back to saturation, and found that cells exhibit characteristic dynamics in surface area to volume ratio (SA/V). SA/V dynamics were conserved across many genetic/chemical perturbations, as well as across species and growth temperatures. We developed a model with a single fitting parameter, the time delay between surface and volume synthesis, that quantitatively explained our SA/V observations, and showed that the time delay was indeed due to differential expression of volume and surface-related genes. The first division after dilution occurred at a tightly controlled SA/V, a previously unrecognized size-control mechanism highlighting the relevance of SA/V. Finally, our time-delay model successfully predicted the quantitative changes in SA/V dynamics due to altered surface area synthesis rates or time delays from translation inhibition. Our minimal model thus provides insight into how cells regulate their morphologies through differential regulation of surface area and volume synthesis and potentiates deep understanding of the connections between growth rate and cell shape in complex environments.
The growth and division of mitochondria during the cell cycle was investigated by a morphometric analysis of electron micrographs of synchronized HeLa cells. The ratio of total outer membrane contour length to cytoplasmic area did not vary significantly during the cell cycle, implying a continuous growth of the mitochondrial outer membrane. The mean fraction of cytoplasmic area occupied by mitochondrial profiles was likewise found to remain constant, indicating that the increase in total mitochondrial volume per cell occurs continuously during interphase, in such a way that the mitochondrial c
Precise control of epithelial tube size is critical for organ function, yet the molecular mechanisms remain poorly understood. Here, we examine the roles of cell growth and a highly conserved organ growth regulatory pathway in controlling the dimensions of the Drosophila tracheal (airway) system, a well-characterized system for investigating epithelial tube morphogenesis. We find that tracheal tube-size is regulated in unexpected ways by the transcription factor Yorkie (Yki, homolog of mammalian YAP and TAZ) and the Salvador/Warts/Hippo (SWH) kinase pathway. Yki activity typically promotes cell division, inhibits apoptosis, and can promote cell growth. However, reducing Yki activity in developing embryos increases rather than decreases the length of the major tracheal tubes, the dorsal trunks (DTs). Similarly, reduction of Hippo pathway activity, which antagonizes Yki, shortens tracheal DTs. yki mutations do not alter DT cell volume or cell number, indicating that Yki and the Hippo pathway regulate cell shape and apical surface area, but not volume. Yki does not appear to act through known tracheal pathways of apical extracellular matrix, septate junctions (SJs), basolateral or tubular polarity. Instead, the Hippo pathway and Yki appear to act downstream or in parallel to SJs because a double mutant combination of an upstream Hippo pathway activator, kibra, and the SJ component sinu have the short tracheal phenotype of a kibra mutant. We demonstrate that the critical target o
Similarly, reduction of Hippo pathway activity, which antagonizes Yki, shortens tracheal DTs. yki mutations do not alter DT cell volume or cell number, indicating that Yki and the Hippo pathway regulate cell shape and apical surface area, but not volume. Yki does not appear to act through known tracheal pathways of apical extracellular matrix, septate junctions (SJs), basolateral or tubular polarity. Instead, the Hippo pathway and Yki appear to act downstream or in parallel to SJs because a double mutant combination of an upstream Hippo pathway activator, kibra, and the SJ component sinu have the short tracheal phenotype of a kibra mutant.
The Drosophila tracheal system serves as a combined pulmonary and vascular system that directly delivers oxygen to tissues through a ramifying network of epithelial tubes. The tracheal system arises from clusters of cells on the surface of the embryo, and these clusters invaginate, undergo one round of cell division and do not divide again. During invagination, tracheal cells retain their apical surfaces and organize into lumen-containing branches. During later embryonic development (stages 15–17), the large dorsal trunk (DT) tubes elongate by changing cell shape and rearranging cell-cell junctions without increasing cell number [8] , [9] .
Second, the basolateral polarity proteins that localize to the SJs antagonize the apical polarity protein Crumbs (Crb), a transmembrane protein that promotes expansion of the tracheal cell apical surface and tube elongation [12] , [16] . In addition to the aECM and polarity pathways, it was recently shown that the highly conserved non-receptor tyrosine kinase Src42 is required for the normal surface area growth of the tracheal apical membrane, and to orient apical growth along the length rather than the circumference of the tube [25] , [26] .
Excessive Src42 activity increases apical surface area in the direction of the length of the tube, which makes tracheal cells more rectangular and increases tracheal length. In contrast, insufficient Src42 activity reduces total apical surface area and remaining membrane growth is misoriented around the circumference of the tube. Thus, Src42 mutant trachea have tracheal tubes that are too short but that are also abnormally large in diameter. The effectors of aECM, polarity, and Src42 pathways have not yet been determined.
Binding of cell death initiators such as Grim, Reaper or Hid to DIAP1 releases the inhibition of Dronc and Ice, which become proteolytically active. Most commonly, activation of caspases leads to cell death, however there are multiple examples of non-apoptotic functions of caspases in Drosophila and mammals [42] – [45] . In this study, we find that Yki has an unexpected role in controlling cell shape during tracheal morphogenesis. While loss of Yki activity typically decreases organ size, loss of Yki increases tracheal dorsal trunk length without increasing tracheal cell volume or number.
Having established a baseline of WT development, we determined tracheal cell number and volume in yki mutants and, for comparison, the SJ mutant cor . Consistent with the almost complete absence of cell death or division during most of tracheal morphogenesis [9] , [10] , cell number was not significantly altered in yki mutants ( Fig. 4J ). Tracheal cell volume in yki mutants was also not statistically different than in WT ( Fig. 3I ). Thus, the increased tracheal length in yki mutants is not driven by increased tracheal cell volume. Surprisingly, in the SJ mutant cor , cell volumes were significantly increased compared to WT ( Fig.
The Drosophila tracheal system provides a powerful model system for investigating non-proliferative/apoptotic roles of the Hippo pathway and Yki/YAP/TAZ in morphogenesis. One puzzling aspect of our results is that previous work by Ghabrial et al . showed that
Plausible pathways that could be regulated by non-apoptotic functions of caspases include apicobasal polarity, which we have previously showed control cell length [12] , [16] , and the endomembrane system, which could potentially mediate changes in apical surface area, cell shape and tube size. Further work will be required to delineate the targets and logic of caspase-mediated tube-size control in the trachea, but the genetic tractability of the Drosophila trachea system make it an excellent system for investigating the non-canonical functions of Yki, DIAP1 and Ice in cell shape control and organ morphogenesis.
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