Review Article | Published:

Sizing up the bacterial cell cycle

Nature Reviews Microbiology volume 15, pages 606620 (2017) | Download Citation

Abstract

It is remarkable how robustly a bacterial species can maintain its preferred size. This capacity is intimately related to control of the cell cycle: cell size and growth rate determine the duration of the cell cycle, which must accommodate the initiation and completion of DNA replication, and the assembly of the division apparatus during steady growth. Although we still lack an integrated view of the interconnections among events in the cell cycle, cell growth and cell size, the development of high-throughput imaging and image-processing protocols has stimulated a renaissance in the field. In this Review, we summarize recent findings, present simple classic models for cell size control, introduce high-throughput data-collection techniques, and explore the mechanisms that coordinate cell size with essential growth and cell cycle processes.

Key points

  • Simple models combined with quantitative time-lapse measurements of cell growth and division are an essential first step towards generating and falsifying mechanistic hypotheses for the homeostasis of cell size and the cell cycle.

  • The recently discovered adder paradigm for cell size control, in which cells add a fixed amount of material between consecutive divisions or DNA replication initiations, has been established in several bacterial species and seems to be widespread. However, the vast majority of bacterial phyla have not yet been investigated.

  • Classic and recent data have indicated that average cell size depends on three key variables: the concentration of DNA replication initiation sites, the average time between DNA replication initiation and cell division, and the mass-doubling time. This dependence accounts for the classic Growth Law, which links cell size to the nutrient quality of the medium, and highlights the need for the simultaneous measurement of a range of cell variables to investigate cell size mutants or perturbations.

  • DnaA, MreB and FtsZ are key regulators of DNA replication initiation, cell growth and cell division, respectively, but currently there is no overarching view of how molecular mechanisms coordinate cell cycle events and cell growth to achieve cell size control and robust genome inheritance.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

    et al. Diverse uncultivated ultra-small bacterial cells in groundwater. Nat. Commun. 6, 6372 (2015).

  2. 2.

    , , & Extreme polyploidy in a large bacterium. Proc. Natl Acad. Sci. USA 105, 6730–6734 (2008).

  3. 3.

    The selective value of bacterial shape. Microbiol. Mol. Biol. Rev. 70, 660–703 (2006).

  4. 4.

    Relationship between cell size and time of initiation of DNA replication. Nature 219, 1077–1079 (1968).

  5. 5.

    et al. What determines cell size? BMC Biol. 10, 101 (2012).

  6. 6.

    Genetic control of cell size at cell division in yeast. Nature 256, 547–551 (1975).

  7. 7.

    , & Concerted control of Escherichia coli cell division. Proc. Natl Acad. Sci. USA 111, 3431–3435 (2014).

  8. 8.

    et al. Division in Escherichia coli is triggered by a size-sensing rather than a timing mechanism. BMC Biol. 12 (2014).

  9. 9.

    Cell size regulation in bacteria. Phys. Rev. Lett. 112, 208102 (2014). An elegant theoretical study of cell size control models that uses extant statistics to identify adder regulation as the mode of size control in E. coli.

  10. 10.

    et al. A constant size extension drives bacterial cell size homeostasis. Cell 159, 1433–1446 (2014). In this study, the adder rule for size control is quantitatively demonstrated by single-cell segmentation and tracking of E. coli and C. crescentus cells in fast-growth regimes.

  11. 11.

    et al. Cell-size control and homeostasis in bacteria. Curr. Biol. 25, 385–391 (2015). In this study, a high-throughput microfluidic device, the mother machine, is applied to E. coli and B. subtilis in fast-growth regimes to establish rigorously the adder rule for size control.

  12. 12.

    , & Synchronous and dichotomous replications of the Bacillus subtilis chromosome during spore germination. Nature 204, 1069–1073 (1964).

  13. 13.

    , & Sequential replication of the Bacillus subtilis chromosome, III. Regulation of initiation. Proc. Natl Acad. Sci. USA 52, 973–980 (1964).

  14. 14.

    , , & On the bacterial life sequence. Cold Spring Harb. Symp. Quant. Biol. 33, 809–822 (1968). This study provides a presentation of the Helmstetter–Cooper model with supporting data and a survey of the relevant classical literature.

  15. 15.

    , & Dependency on medium and temperature of cell size and chemical composition during balanced growth of Salmonella typhimurium. J. Gen. Microbiol. 19, 592–606 (1958). A seminal study that first identifies the Growth Law, the exponential scaling of cell mass with growth rate as the nutritional composition of the medium is varied.

  16. 16.

    , , , Baltekin, Ö. & The synchronization of replication and division cycles in individual E. coli cells. Cell 166, 729–739 (2016). In this study, E. coli is studied in slow-growth regimes, providing evidence that replication initiation is triggered at a fixed cell volume per oriC, thus producing sizer regulation; modelling and data together demonstrate that this mechanism could potentially account for adder regulation in fast-growth regimes.

  17. 17.

    , , & Cell size and the initiation of DNA replication in bacteria. PLoS Genet. 8, e1002549 (2012). This innovative experimental study presents DNA replication and division statistics for E. coli and B. subtilis cell size mutants, and identifies fundamental differences in how cell size is altered in the mutants.

  18. 18.

    et al. Interrogating the Escherichia coli cell cycle by cell dimension perturbations. Proc. Nat. Acad. Sci. USA 113, 15000–15005 (2016). In this study, FtsZ and MreB levels are shown to influence cell size by adjusting the time period between the termination of a round of DNA replication and the corresponding cell division (the D-period); furthermore, evidence is presented for cell-size regulation according to volume or a property that scales proportionally with volume.

  19. 19.

    & Simultaneous regulation of cell size and chromosome replication in bacteria. Front. Microbiol. 6, 662–672 (2015).

  20. 20.

    , & Genome-wide phenotypic analysis of growth, cell morphogenesis and cell cycle events in Escherichia coli. Preprint at bioRxiv (2017).

  21. 21.

    et al. Invariance of initiation mass and predictability of cell size in Escherichia coli. Curr. Biol. 27, 1278–1287 (2017). This study provides strong evidence for the General Growth Law in nutrient-rich media, indicating that the C-period and D-period, the mass-doubling time and oriC concentration combine to determine overall cell size; moreover, oriC concentration is shown to be approximately constant under a broad range of antibiotic perturbations.

  22. 22.

    & Cell length, nucleoid separation, and cell division of rod-shaped and spherical cells of Escherichia coli. J. Bacteriol. 171, 4633–4639 (1989).

  23. 23.

    & A model for statistics of the cell division process. J. Gen. Microbiol. 29, 435–454 (1962).

  24. 24.

    Relation between cell growth and cell division. II. The effect of cell size on cell growth rate and generation time in Amoeba proteus. Exp. Cell Res. 11, 86–94 (1956).

  25. 25.

    & Control of cell size at division in fission yeast by a growth-modulated size control over nuclear division. Exp. Cell Res. 107, 377–386 (1977).

  26. 26.

    Control of cell size and cycle time in Schizosaccharomyces pombe. J. Cell Sci. 24, 51–67 (1977).

  27. 27.

    et al. Measuring single-cell gene expression dynamics in bacteria using fluorescence time-lapse microscopy. Nat. Protoc. 7, 80–88 (2012).

  28. 28.

    et al. Oufti: An integrated software package for high-accuracy, high-throughput quantitative microscopy analysis. Mol. Microbiol. 99, 767–777 (2015).

  29. 29.

    et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7, R100 (2006).

  30. 30.

    , , , & Single-cell physiology. Annu. Rev. Biophys. 44, 123–142 (2015).

  31. 31.

    , , , & SuperSegger: robust image segmentation, analysis and lineage tracking of bacterial cells. Mol. Microbiol. 102, 690–700 (2016).

  32. 32.

    , , , & Correlation between size and age at different events in the cell division cycle of Escherichia coli. J. Bacteriol. 143, 1241–1252 (1980). A pioneering study that computes correlations among cell cycle and cell size variables in slow-growing synchronized E. coli cells, and deduces from population-level statistics exponential cell growth, a constant average cell size at replication initiation, and a positive correlation between birth and division sizes.

  33. 33.

    & Skew or third moment of bacterial generation times. Arch. Microbiol. 169, 43–51 (1998).

  34. 34.

    et al. A noisy linear map underlies oscillations in cell size and gene expression in bacteria. Nature 523, 357–360 (2015).

  35. 35.

    , & The bacterial cytoskeleton: an intermediate filament-like function in cell shape. Cell 115, 705–713 (2003).

  36. 36.

    , & Mathematics of cell division in Escherichia coli: comparison between sloppy-size and incremental-size kinetics. Curr. Top. Mol. Gen. 1, 187–194 (1993).

  37. 37.

    , & Cell-size homeostasis and the incremental rule in a bacterial pathogen. Biophys. J. 109, 521–528 (2015).

  38. 38.

    et al. Single-cell analysis of growth and cell division of the anaerobe Desulfovibrio vulgaris Hildenborough. Front. Microbiol. 6, 1378 (2015).

  39. 39.

    & Cell-cycle progression and the generation of asymmetry in Caulobacter crescentus. Nat. Rev. Microbiol. 2, 325–337 (2004).

  40. 40.

    et al. Scaling laws governing stochastic growth and division of single bacterial cells. Proc. Natl Acad. Sci. USA 111, 15912–15917 (2014).

  41. 41.

    & Cell-size maintenance: universal strategy revealed. Trends Microbiol. 23, 4–6 (2015).

  42. 42.

    Sculpting the bacterial cell. Curr. Biol. 19, R812–R822 (2009).

  43. 43.

    et al. Rod-like bacterial shape is maintained by feedback between cell curvature and cytoskeletal localization. Proc. Natl Acad. Sci. USA 111, E1025–E1034 (2014).

  44. 44.

    , , , & Mutations in the nucleotide binding pocket of MreB can alter cell curvature and polar morphology in Caulobacter. Mol. Microbiol. 81, 368–394 (2011).

  45. 45.

    et al. The tubulin homologue FtsZ contributes to cell elongation by guiding cell wall precursor synthesis in Caulobacter crescentus. Mol. Microbiol. 64, 938–952 (2007).

  46. 46.

    , , , & Single-cell dynamics of the chromosome replication and cell division cycles in mycobacteria. Nat. Commun. 4, 2470 (2013).

  47. 47.

    et al. Long-term microfluidic tracking of coccoid cyanobacterial cells reveals robust control of division timing. BMC Biol. 15, 11 (2017).

  48. 48.

    et al. Robust growth of Escherichia coli. Curr. Biol. 20, 1099–1103 (2010).

  49. 49.

    Size sensors in bacteria, cell cycle control, and size control. Front. Microbiol. 6, 515 (2015).

  50. 50.

    & A fixed distance for separation of newly replicated copies of oriC in Bacillus subtilis: implications for co-ordination of chromosome segregation and cell division. Mol. Microbiol. 28, 981–990 (1998).

  51. 51.

    , & A division inhibitor and a topological specificity factor coded for by the minicell locus determine proper placement of the division septum in E. coli. Cell 56, 641–649 (1989).

  52. 52.

    & FtsZ ring clusters in min and partition mutants: role of both the Min system and the nucleoid in regulating FtsZ ring localization. Mol. Microbiol. 32, 315–326 (1999).

  53. 53.

    & Autorepressor model for control of DNA replication. Nature New Biol. 241, 133–135 (1973).

  54. 54.

    , & Control of DNA synthesis in bacteria. Symp. Soc. Gen. Microbiol. 19, 263–297 (1969).

  55. 55.

    & The biosynthetic basis of cell size control. Trends Cell Biol. 25, 793–802 (2015).

  56. 56.

    & Metabolism, cell growth and the bacterial cell cycle. Nat. Rev. Microbiol. 7, 822–827 (2009).

  57. 57.

    , , & Superresolution imaging of ribosomes and RNA polymerase in live Escherichia coli cells. Mol. Microbiol. 85, 21–38 (2012).

  58. 58.

    et al. Timing of Z-ring localization in Escherichia coli. Phys. Biol. 8, 066003 (2011).

  59. 59.

    , & Cell size control in bacteria. Curr. Biol. 22, R340–R349 (2012). A scholarly review that details several topics briefly presented in this Review, especially the relationships between cell size and nutrient availability, and between cell size and ftsZ expression.

  60. 60.

    , & The choreographed dynamics of bacterial chromosomes. Trends Microbiol. 13, 221–228 (2005).

  61. 61.

    et al. Spatial and temporal organization of replicating Escherichia coli chromosomes. Mol. Microbiol. 49, 731–743 (2003).

  62. 62.

    & Chromosome and replisome dynamics in E. coli: loss of sister cohesion triggers global chromosome movement and mediates chromosome segregation. Cell 121, 899–911 (2005).

  63. 63.

    , , & Use of thymine limitation and thymine starvation to study bacterial physiology and cytology. J. Bacteriol. 188, 1667–1679 (2006).

  64. 64.

    , , & Precise determinations of C and D periods by flow cytometry in Escherichia coli K-12 and B/r. Microbiology 149, 1001–1010 (2003).

  65. 65.

    , & Escherichia coli DNA distributions measured by flow cytometry and compared with theoretical computer simulations. J. Bacteriol. 163, 661–668 (1985).

  66. 66.

    & Chromosome replication and the division cycle of Escherichia coli. J. Mol. Biol. 31, 519–540 (1968).

  67. 67.

    Rate of DNA synthesis during the division cycle of Escherichia coli B/r. J. Mol. Biol. 24, 417–427 (1967).

  68. 68.

    & Induction of replication by thymine starvation at the chromosome origin in Escherichia coli. J. Mol. Biol. 9, 288–307 (1964).

  69. 69.

    , & Timing of initiation of chromosome replication in individual Escherichia coli cells. EMBO J. 5, 1711–1717 (1986).

  70. 70.

    , , , & Replication and segregation of an Escherichia coli chromosome with two replication origins. Proc. Natl Acad. Sci. USA 108, 243–250 (2011).

  71. 71.

    The organization of the bacterial genome. Annu. Rev. Genet. 42, 211–233 (2008).

  72. 72.

    , & Initiation and velocity of chromosome replication in Escherichia coli B/r and K-12. J. Bacteriol. 180, 265–273 (1998).

  73. 73.

    Synchronization of chromosome dynamics and cell division in bacteria. Cold Spring Harb. Perspect. Biol. 2, a000331 (2010).

  74. 74.

    & Coupling the cell cycle to cell growth. EMBO Rep. 4, 757–760 (2003).

  75. 75.

    , , & Regulation of bacterial cell division: temperature-sensitive mutants of Escherichia coli that are defective in septum formation. J. Bacteriol. 123, 693–703 (1975).

  76. 76.

    & Cell-size control. Cold Spring Harb. Perspect. Biol. 8, a019083 (2016). A recent review that discusses our current understanding of cell size control in several highly divergent organisms, including bacteria.

  77. 77.

    , & The transition between different physiological states during balanced growth of Salmonella typhimurium. J. Gen. Microbiol. 19, 607–616 (1958).

  78. 78.

    Cell division and DNA replication following a shift to a richer medium. J. Mol. Biol. 43, 1–11 (1969).

  79. 79.

    Control of cell length in Bacillus subtilis. J. Bacteriol. 123, 7–19 (1975).

  80. 80.

    , , & Bacillus subtilis cell cycle as studied by fluorescence microscopy: constancy of cell length at initiation of DNA replication and evidence for active nucleoid partitioning. J. Bacteriol. 180, 547–555 (1998).

  81. 81.

    , , & Coordinating DNA replication initiation with cell growth: differential roles for DnaA and SeqA proteins. Proc. Natl Acad. Sci. USA 93, 12206–12211 (1996).

  82. 82.

    & Changes in cell size and shape associated with changes in the replication time of the chromosome of Escherichia coli. J. Bacteriol. 114, 824–837 (1973).

  83. 83.

    , & Growth rate-dependent control of chromosome replication initiation in Escherichia coli. J. Bacteriol. 145, 1232–1238 (1981).

  84. 84.

    et al. Inflating bacterial cells by increased protein synthesis. Mol. Syst. Biol. 11, 836 (2015).

  85. 85.

    & An examination of the Cooper-Helmstetter theory of DNA replication in bacteria and its underlying assumptions. J. Theor. Biol. 69, 645–654 (1977).

  86. 86.

    , , , & The initiation mass for DNA replication in Escherichia coli K-12 is dependent on growth rate. EMBO J. 13, 2097–2102 (1994).

  87. 87.

    et al. Effects of oriC relocation on control of replication initiation in Bacillus subtilis. Microbiology 155, 3070–3082 (2009).

  88. 88.

    , & Step by step, cell by cell: quantification of the bacterial cell cycle. Trends Microbiol. 25, 250–256 (2017).

  89. 89.

    Point of view: Is cell size a spandrel? eLife 6, e22186 (2017).

  90. 90.

    , , , & Stochasticity and homeostasis in the E. coli replication and division cycle. Sci. Rep. 5, 18261 (2015).

  91. 91.

    Self-consistent examination of Donachie's constant initiation size at the single-cell level. Front. Microbiol. 6, 1349 (2015).

  92. 92.

    , D. & The two chromosomes of Vibrio cholerae are initiated at different time points in the cell cycle. EMBO J. 26, 3124–3131 (2007).

  93. 93.

    , & Replication patterns and organization of replication forks in Vibrio cholerae. Microbiology 157, 695–708 (2001).

  94. 94.

    & Regulating DNA replication in bacteria. Cold Spring Harb. Perspect. Biol. 5, a012922 (2013). A detailed review of the molecular regulation of replication initiation and DnaA spatiotemporal kinetics during the cell cycle.

  95. 95.

    et al. A nucleotide switch in the Escherichia coli DnaA protein initiates chromosomal replication: evidence from a mutant DnaA protein defective in regulatory ATP hydrolysis in vitro and in vivo. J. Biol. Chem. 277, 14986–14995 (2002).

  96. 96.

    , & Autoregulation of the dnaA gene of Escherichia coli K12. Mol. Gen. Genet. 200, 442–450 (1985).

  97. 97.

    & DnaA binding locus datA promotes DnaA-ATP hydrolysis to enable cell cycle-coordinated replication initiation. Proc. Natl Acad. Sci. USA 110, 936–941 (2013).

  98. 98.

    , , & Autoregulation of the dnaA-dnaN operon and effects of DnaA protein levels on replication initiation in Bacillus subtilis. J. Bacteriol. 183, 3833–3841 (2001).

  99. 99.

    , & Autoregulation of the DNA replication gene dnaA in E. coli K-12. Cell 40, 159–169 (1985).

  100. 100.

    , Morigen & DnaA protein interacts with RNA polymerase and partially protects it from the effect of rifampicin. Mol. Microbiol. 71, 1018–1030 (2008).

  101. 101.

    & Multiple regulatory systems coordinate DNA replication with cell growth in Bacillus subtilis. PLoS Genet. 10, e1004731 (2014).

  102. 102.

    et al. Initiator (DnaA) protein concentration as a function of growth rate in Escherichia coli and Salmonella typhimurium. J. Bacteriol. 173, 5194–5199 (1991).

  103. 103.

    & Regulated degradation of chromosome replication proteins DnaA and CtrA in Caulobacter crescentus. Mol. Microbiol. 55, 1233–1245 (2005).

  104. 104.

    , & Genetic and physiological characterization of a spontaneous mutant of Escherichia coli B/r with aberrant control of deoxyribonucleic acid replication. J. Bacteriol. 145, 1239–1248 (1981).

  105. 105.

    , , , & The DnaA protein determines the initiation mass of Escherichia coli K-12. Cell 57, 881–889 (1989).

  106. 106.

    , , , & Initiation of DNA replication in Escherichia coli after overproduction of the DnaA protein. Mol. Gen. Genet. 218, 50–56 (1989).

  107. 107.

    & Three distinct chromosome replication states are induced by increasing concentrations of DnaA protein in Escherichia coli. J. Bacteriol. 175, 6537–6545 (1993).

  108. 108.

    , , , & The DnaA protein is not the limiting factor for initiation of replication in Escherichia coli. PLoS Genet. 11, e1005276 (2015).

  109. 109.

    & DnaA initiator - also a transcription factor. Mol. Microbiol. 24, 1–6 (1997).

  110. 110.

    , , , & A transcriptional response to replication status mediated by the conserved bacterial replication protein DnaA. Proc. Natl Acad. Sci. USA 102, 12932–12937 (2005).

  111. 111.

    , & DnaA coordinates replication initiation and cell cycle transcription in Caulobacter crescentus. Mol. Microbiol. 58, 1340–1353 (2005).

  112. 112.

    et al. A novel regulatory mechanism couples deoxyribonucleotide synthesis and DNA replication in Escherichia coli. EMBO J. 25, 1137–1147 (2006).

  113. 113.

    To divide or not to divide: control of the bacterial cell cycle by environmental cues. Curr. Opin. Microbiol. 18, 54–60 (2014).

  114. 114.

    FtsZ and the division of prokaryotic cells and organelles. Nat. Rev. Mol. Cell. Biol. 6, 862–871 (2005).

  115. 115.

    , , & The division inhibitor EzrA contains a seven-residue patch required for maintaining the dynamic nature of the medial FtsZ ring. J. Bacteriol. 189, 9001–9010 (2007).

  116. 116.

    , & Dependency of Escherichia coli cell-division size, and independency of nucleoid segregation on the mode and level of ftsZ expression. Mol. Microbiol. 20, 1093–1098 (1996).

  117. 117.

    & Overproduction of FtsZ induces minicell formation in E. coli. Cell 42, 941–999 (1985).

  118. 118.

    & Molecular cloning and characterization of the pgm gene encoding phosphoglucomutase of Escherichia coli. J. Bacteriol. 176, 5847–5851 (1994).

  119. 119.

    et al. A metabolic sensor governing cell size in bacteria. Cell 130, 335–347 (2007).

  120. 120.

    , & The ftsA* gain-of-function allele of Escherichia coli and its effects on the stability and dynamics of the Z-ring. Microbiology 153, 814–825 (2007).

  121. 121.

    & Metabolism shapes the cell. J. Bacteriol. 199, e00039–17 (2017).

  122. 122.

    , , & Rapid assembly dynamics of the Escherichia coli FtsZ-ring demonstrated by fluorescence recovery after photobleaching. Proc. Natl Acad. Sci. USA 99, 3171–3175 (2002).

  123. 123.

    & Bacterial cell division: assembly, maintenance and disassembly of the Z ring. Nat. Rev. Microbiol. 7, 642–653 (2009).

  124. 124.

    & Nucleoid occlusion and bacterial cell division. Nat. Rev. Microbiol. 10, 8–12 (2012).

  125. 125.

    & Growth rate-dependent regulation of medial FtsZ ring formation. J. Bacteriol. 185, 2826–2834 (2003).

  126. 126.

    , & Concentration and assembly of the division ring proteins FtsZ, FtsA, and ZipA during the Escherichia coli cell cycle. J. Bacteriol. 185, 3344–3351 (2003).

  127. 127.

    , & Cell cycle regulation and cell type-specific localization of the FtsZ division initiation protein in Caulobacter. Proc. Natl Acad. Sci. USA 93, 6314–6319 (1996).

  128. 128.

    , , , & Cell cycle-dependent transcriptional and proteolytic regulation of FtsZ in Caulobacter. Genes Dev. 12, 880–893 (1998).

  129. 129.

    et al. Proteomic analysis of the bacterial cell cycle. Proc. Natl Acad. Sci. USA 98, 4681–4686 (2001).

  130. 130.

    Growth of the stress-bearing and shape-maintaining murein sacculus of Escherichia coli. Microbiol. Mol. Biol. Rev. 62, 181–203 (1998).

  131. 131.

    & Relative rates of surface and volume synthesis set bacterial cell size. Cell 165, 1479–1492 (2016). This study combines experimental data and phenomenological modelling to convincingly argue that various rod-shaped bacteria increase surface area at a condition-dependent rate proportional to cell volume, causing cells to regress to particular surface area to volume ratios over multiple cell cycles.

  132. 132.

    , & The composition of the murein of Escherichia coli. J. Biol. Chem. 263, 10088–10095 (1988).

  133. 133.

    & MreB: pilot or passenger of cell wall synthesis? Trends Microbiol. 20, 74–79 (2012).

  134. 134.

    et al. Systematic perturbation of cytoskeletal function reveals a linear scaling relationship between cell geometry and fitness. Cell Rep. 9, 1528–1537 (2014).

  135. 135.

    & Direct interaction of FtsZ and MreB is required for septum synthesis and cell division in Escherichia coli. EMBO J. 32, 1953–1965 (2013).

  136. 136.

    , , , & MreB actin-mediated segregation of a specific region of a bacterial chromosome. Cell 120, 329–341 (2005).

  137. 137.

    et al. Actin homolog MreB and RNA polymerase interact and are both required for chromosome segregation in Escherichia coli. Genes Dev. 20, 113–124 (2006).

  138. 138.

    , & A Caulobacter MreB mutant with irregular cell shape exhibits compensatory widening to maintain a preferred surface area to volume ratio. Mol. Microbiol. 94, 988–1005 (2014).

  139. 139.

    et al. Mechanical crack propagation drives millisecond daughter cell separation in Staphylococcus aureus. Science 348, 574–578 (2015).

  140. 140.

    et al. A comprehensize, CRISPR-based approach to functional analysis of essential genes in bacteria. Cell 165, 1493–1506 (2016).

  141. 141.

    et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, 2006.0008 (2006).

  142. 142.

    On the average cellular volume in synchronized cell populations. Bull. Math. Biophys. 32, 459–473 (1970).

  143. 143.

    , , & Growth, cell and nuclear divisions in some bacteria. J. Gen. Microbiol. 29, 421–434 (1962).

  144. 144.

    et al. Universal protein distributions in a model of cell growth and division. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 92, 042713 (2015).

  145. 145.

    , , , & Cell growth and size homeostasis in proliferating animal cells. Science 325, 167–171 (2009).

  146. 146.

    , & Adder and a coarse-grained approach to cell size homeostasis in bacteria. Curr. Opin. Cell Biol. 38, 38–44 (2016).

  147. 147.

    , & Single-cell analysis of growth in budding yeast and bacteria reveals a common size regulation strategy. Curr. Biol. 26, 356–361 (2016).

  148. 148.

    et al. Advanced methods of microscope control using MicroManager software. J. Biol. Methods 1, e11 (2014).

  149. 149.

    Apples, oranges and unknown fruit. Nat. Rev. Microbiol. 4, 876 (2006).

  150. 150.

    , , & Sequential evolution of bacterial morphology by co-option of a developmental regulator. Nature 506, 489–493 (2014).

  151. 151.

    & Environmental control of cell size at division. Curr. Opin. Cell Biol. 24, 838–844 (2012).

  152. 152.

    , & Diversity in (p)ppGpp metabolism and effectors. Curr. Opin. Microbiol. 24, 72–79 (2015).

  153. 153.

    et al. Fatty acid availability sets cell envelope capacity and dictates microbial cell size. Curr. Biol. 27, 1757–1767.e5 (2017).

  154. 154.

    , , & A moonlighting enzyme links Escherichia coli cell size with central metabolism. PLoS Genet. 9, e1003663 (2013).

  155. 155.

    et al. A new view of the tree of life. Nat. Microbiol. 1, 16048 (2016).

  156. 156.

    & Chromosome replication, cell growth, division and shape: a personal perspective. Front. Microbiol. 6, 756 (2015).

  157. 157.

    et al. Biphasic growth dynamics control cell division in Caulobacter crescentus. Nat. Microbiol. 2, 17116 (2017).

Download references

Acknowledgements

The authors thank the Huang laboratory, L. Harris and P. Levin for helpful discussions. Work was supported, in part, by NSF CAREER Award MCB-1149328 (to K.C.H.) and the Allen Discovery Center at Stanford University on Systems Modeling of Infection (to K.C.H.). The authors regret that, owing to the broad scope of this Review and space constraints, many excellent and arguably relevant studies could not be cited.

Author information

Affiliations

  1. Sainsbury Laboratory, University of Cambridge, Cambridge CB2 1LR, UK.

    • Lisa Willis
  2. Department of Bioengineering, Stanford University.

    • Lisa Willis
    •  & Kerwyn Casey Huang
  3. Department of Microbiology and Immunology, Stanford University, Stanford, California 94305, USA.

    • Kerwyn Casey Huang

Authors

  1. Search for Lisa Willis in:

  2. Search for Kerwyn Casey Huang in:

Contributions

L.W. and K.C.H. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lisa Willis or Kerwyn Casey Huang.

Glossary

oriC

The origin of replication; a highly conserved DNA sequence on the bacterial chromosome from which bidirectional DNA replication is initiated.

Growth Law

For the model bacteria Escherichia coli and Salmonella enterica subsp. enterica serovar Typhimurium, average cell size increases as the nutritional quality of the growth medium improves and hence as cells grow faster. This size increase depends on growth rate alone and not on the chemical composition of the medium.

DnaA

A highly conserved protein that triggers the initiation of DNA replication following binding to ATP and multiple specific DnaA-binding sequences within oriC. DnaA is a strong candidate for participating in cell size control.

FtsZ

A bacterial homologue of eukaryotic tubulin and the key regulator of cell division.

MreB

A bacterial homologue of eukaryotic actin that functions as the spatial scaffold for the patterning of insertion of new cell wall material in many rod-shaped species.

Exponential growth

Cells that grow exponentially have an absolute growth rate that is proportional to cell size throughout the cell cycle. Other growth kinetics are possible, such as linear kinetics, in which the absolute growth rate is constant throughout the cell cycle, regardless of cell size.

Min proteins

The Escherichia coli Min system (proteins MinC, MinD and MinE) participates in locating the septum at mid-cell through spatiotemporal oscillations of membrane-bound Min proteins that inhibit FtsZ assembly at the cell poles.

Replisomes

Molecular complexes that are located at a replication fork that carry out DNA replication.

Origin firing

The beginning of a new round of DNA replication when, facilitated by DnaA, the oriCs unwind for replisome loading.

Mother machine

A microfluidic device in which nutrients are continually replenished and cells are trapped in narrow channels, continually growing and dividing at a steady density. This device enables cell tracking over many generations in a stable environment.

Z-ring

A band of polymerized FtsZ at mid-cell, the assembly of which is the first known step in cell division.

Membrane elution technique

Method for eluting newborn cells from a growing culture (also known as the baby machine) in which cells are initially bound to a membrane. As the culture grows, only newborn non-membrane- bound sister cells are eluted. The temporal order of cell elution is inversely related to cell age, yielding correlations between cell age and other cellular variables, such as DNA synthesis rate, that are pulse-labelled before elution.

SOS response

An inducible DNA damage repair system that is widely present among bacteria and that is comprised of two key proteins in Escherichia coli: a default repressor and a DNA damage-induced de-repressor.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrmicro.2017.79