Intracellular chemical gradients: morphing principle in bacteria
© Endres.; licensee BioMed Central Ltd. 2012
Received: 30 August 2012
Accepted: 4 September 2012
Published: 7 September 2012
Advances in computational biology allow systematic investigations to ascertain whether internal chemical gradients can be maintained in bacteria – an open question at the resolution limit of fluorescence microscopy. While it was previously believed that the small bacterial cell size and fast diffusion in the cytoplasm effectively remove any such gradient, a new computational study published in BMC Biophysics supports the emerging view that gradients can exist. The study arose from the recent observation that phosphorylated CtrA forms a gradient prior to cell division in Caulobacter crescentus, a bacterium known for its complicated cell cycle. Tropini et al. (2012) postulate that such gradients can provide an internal chemical compass, directing protein localization, cell division and cell development. More specifically, they describe biochemical and physical constraints on the formation of such gradients and explore a number of existing bacterial cell morphologies. These chemical gradients may limit in vitro analyses, and may ensure timing control and robustness to fluctuations during critical stages in cell development.
Previously, it was believed that chemical gradients inside a small micron-sized bacterial cell are quickly wiped out by fast diffusion. This is similar to the notion that bacteria are unable to directly sense external spatial gradients, only temporally by comparison measurements while swimming. However, such subtle questions are difficult to assess, and this is where computational biology can help : computational analysis can guide difficult experiments and allow us to scan through multiple parameters in search for interesting mathematical solutions. For instance, such analysis showed that spatial chemical gradients can, in principle, be sensed by bacteria after all [17, 18] and an example was later found . The exploration of the physical limits of sensing was then also extended to sensing of external chemical gradients with unexpected predictions .
Tropini et al.  ask under what conditions a localised source and sink on two cell ends can lead to a significant chemical gradient. Extending previous studies by others , they systematically explored different cell geometries, including round, rod-shaped, curved, Y-shaped and dividing cells. They also investigated biochemical effects such as enzyme localization and saturation, and explored large parameter regimes to address robustness. Their principal finding is that gradients can exist as long as the kinetics of the source and sink are on timescales faster than the typical time required to diffuse across the length of the cell. However, due to restrictions from numerical solutions of the reaction-diffusion equations, no linear stability analysis could be done, e.g. to see how gradients respond to perturbations. Additionally, due to the continuum approximation for molecular concentrations, no stochastic fluctuations could be included to see how molecular noise affects gradients . Does this lessen the impact of the paper? – In light of the advanced computational algorithms used, we would argue no. The authors offer a systematic exploration of parameter values to investigate robustness (and effectively the influence of noise on a gradient), and connect to actual biological examples from various bacterial species. Furthermore, while other molecular components and structures such as chromosomes were neglected, molecular crowding would actually favour the establishment of gradients by increasing the time scale for movement between the poles.
If cell division provides asymmetry anyway, e.g. via old and new cell poles, why deploy gradients prior to cell division? For instance, in C. crescentus second messanger cyclic-di-GMP is asymmetrically distributed between the two daughter cells right after cell division for motility and organelle formation . The authors propose an intriguing possibility. Intracellular gradients may ensure timing control and robustness to fluctuations during the life of the cell prior to cell division. Bacteria and fission yeast, both of which have cell walls, need to actively regulate cell division - otherwise widespread cell geometries and large fluctuations would be unavoidable . Utilising a gradient might also be better for cell-size control than a threshold-crossing mechanism of a uniformly distributed protein using dilution during growth . Of practical importance for the experimentalist, these chemical gradients may limit the usefulness of in vitro analyses since concentrations are homogenised. However, the study also cautions in vivo analyses using GFP-tagged proteins, as changing the size of proteins may alter their diffusion constants .
Lewis Wolpert had the foresight that morphogen gradients can provide the necessary positional information for structuring the developing embryo [28, 29]. The current study extends this powerful idea to tiny bacteria. Furthermore, the results by Tropini et al. highlight the utility of mathematical modelling in future studies of intracellular organization in bacteria, and illustrate the complex spatial patterning that can be achieved even in the absence of membrane compartmentalization.
We are grateful to Victor Sourjik for comments on the manuscript. This work was supported by the Leverhulme Trust grant RPG-181 and ERC Starting Grant 280492-PPHPI.
- Bassler BL, Losick R: Bacterially speaking. Cell. 2006, 125: 237-246. 10.1016/j.cell.2006.04.001.View Article
- Cabeen MT, Jacobs-Wagner C: The bacterial cytoskeleton. Annu Rev Genet. 2010, 44: 365-392. 10.1146/annurev-genet-102108-134845.View Article
- Porcher A, Dostatni N: The bicoid morphogen system. Curr Biol. 2010, 20: R249-R254.
- Wartlick O, Mumcu P, Jülicher F, Gonzalez-Gaitan M: Understanding morphogenetic growth control – lessons from flies. Nat Rev Mol Cell Biol. 2011, 12: 594-604. 10.1038/nrm3169.View Article
- Chen YE, Tropini C, Jonas K, Tsokos CG, Huang KC, Laub MT: Spatial gradient of protein phosphorylation underlies replicative asymmetry in a bacterium. Proc Natl Acad Sci USA. 2011, 108: 1052-1057. 10.1073/pnas.1015397108.View ArticleADS
- Robbins JR, Monack D, McCallum SJ, Vegas A, Pham E, Goldberg MB, Theriot JA: The making of a gradient: IcsA (VirG) polarity in Shigella flexneri. Mol Microbiol. 2001, 41: 861-872.View Article
- Halatek J, Frey E: Highly canalized MinD transfer and MinE sequestration explain the origin of robust MinCDE-protein dynamics. Cell Rep. 2012, 1: 741-752. 10.1016/j.celrep.2012.04.005.View Article
- Martin SG, Berthelot-Grosjean M: Polar gradients of the DYRK-family kinase Pom1 couple cell length with the cell cycle. Nature. 2009, 459: 852-856. 10.1038/nature08054.View ArticleADS
- Moseley JB, Mayeux A, Paoletti A, Nurse P: A spatial gradient coordinates cell size and mitotic entry in fission yeast. Nature. 2009, 459: 857-860. 10.1038/nature08074.View ArticleADS
- Howard M: How to build a robust intracellular concentration gradient. Trends Cell Biol. 2012, 22: 311-317. 10.1016/j.tcb.2012.03.002.View Article
- Endres RG: Polar chemoreceptor clustering by coupled trimers of dimers. Biophys J. 2009, 96: 453-463. 10.1016/j.bpj.2008.10.021.View Article
- Sourjik V, Armitage JP: Spatial organization in bacterial chemotaxis. EMBO J. 2010, 29: 2724-2733. 10.1038/emboj.2010.178.View Article
- Lipkow K, Andrews SS, Bray D: Simulated diffusion of phosphorylated CheY through the cytoplasm of Escherichia coli. J Bacteriol. 2005, 187: 45-53. 10.1128/JB.187.1.45-53.2005.View Article
- Turing AM: The chemical basis of morphogenesis. Phil Trans Roy Soc B. 1952, 237: 37-72. 10.1098/rstb.1952.0012.View ArticleADS
- Cross M, Greenside H: Pattern formation and dynamics in nonequilibrium systems. 2009, Pattern formation and dynamics in nonequilibrium systems, Cambridge University PressView Article
- Cohen JE: Mathematics is biology's next microscope, only better; biology is mathematics' next physics, only better. PLoS Biol. 2004, 2: e439-10.1371/journal.pbio.0020439.View Article
- Berg HC, Purcell EM: Physics of chemoreception. Biophys J. 1977, 20: 193-219. 10.1016/S0006-3495(77)85544-6.View Article
- Dusenbery DB: Spatial sensing of stimulus gradients can be superior to temporal sensing for free-swimming bacteria. Biophys J. 1998, 74: 2272-2277. 10.1016/S0006-3495(98)77936-6.View Article
- Thar R, Kühl M: Bacteria are not too small for spatial sensing of chemical gradients: An experimental evidence. Proc Natl Acad Sci USA. 2003, 100: 5748-5753. 10.1073/pnas.1030795100.View ArticleADS
- Endres RG, Wingreen NS: Accuracy of direct gradient sensing by single cells. Proc Natl Acad Sci USA. 2008, 105: 15749-15754. 10.1073/pnas.0804688105.View ArticleADS
- Tropini C, Rabbani N, Huang KC: Physical constraints on the establishment of intracellular spatial gradients in bacteria. BMC Biophys. 2012, 5: 17-10.1186/2046-1682-5-17.View Article
- Brown GC, Kholodenko BN: Spatial gradients of cellular phospho-proteins. FEBS Lett. 1999, 457: 452-454. 10.1016/S0014-5793(99)01058-3.View Article
- Kerr RA, Levine H, Sejnowski TJ, Rappel WJ: Division accuracy in a stochastic model of Min oscillations in Escherichia coli. Proc Natl Acad Sci USA. 2006, 103: 347-352. 10.1073/pnas.0505825102.View ArticleADS
- Christen M, Kulasekara HD, Christen B, Kulasekara BR, Hoffman LR, Miller SI: Asymmetrical distribution of the second messenger c-di-GMP upon bacterial cell division. Science. 2010, 328: 1295-1297. 10.1126/science.1188658.View ArticleADS
- Fantes PA, Nance P: Division timing, models and mechanisms. 1981, In The Cell Cycle, John PCL, Cambridge University Press, 11-33.
- Tostevin F: Precision of sensing cell length via concentration gradients. Biophys J. 2011, 100: 294-303. 10.1016/j.bpj.2010.11.046.View Article
- Kumar M, Mommer MS, Sourjik V: Mobility of cytoplasmic, membrane, and DNA-binding proteins in Escherichia coli. Biophys J. 2010, 98: 552-559. 10.1016/j.bpj.2009.11.002.View Article
- Wolpert LJ: Positional information and the spatial pattern of cellular differentiation. Theor Biol. 1969, 25: 1-47. 10.1016/S0022-5193(69)80016-0.View Article
- Jaeger J, Martinez-Arias A: Getting the measure of positional information. PLoS Biol. 2009, 7: e81-10.1371/journal.pbio.1000081.View Article
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