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The mechanism of cell differentiation in Bacillus subtilis


Sporulation in Bacillus subtilis serves as a model for the development of two different cell types from a single cell1. Although much information has been accumulated about the mechanisms that initiate the developmental programmes2, important questions remain that can be answered only by quantitative analysis. Here we develop, with the help of existing and new experimental results, a mathematical model that reproduces published in vitro experiments and explains how the activation of the key transcription factor is regulated. The model identifies the difference in volume between the two cell types as the primary trigger for determining cell fate. It shows that this effect depends on the allosteric behaviour of a key protein kinase and on a low rate of dephosphorylation by the corresponding phosphatase; both predicted effects are confirmed experimentally.

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Figure 1: Regulation of σ F release during sporulation.
Figure 2: SpoIIAB is an allosteric protein.
Figure 3: Verification of the model with in vitro data.
Figure 4: Mechanism of prespore-specific σ F –RNA-polymerase holoenzyme formation.


  1. Hilbert, D. W. & Piggot, P. J. Compartmentalization of gene expression during Bacillus subtilis spore formation. Microbiol. Mol. Biol. Rev. 68, 234–262 (2004)

    CAS  Article  Google Scholar 

  2. Yudkin, M. D. & Clarkson, J. Differential gene expression in genetically identical sister cells: the initiation of sporulation in Bacillus subtilis. Mol. Microbiol. 56, 578–589 (2005)

    CAS  Article  Google Scholar 

  3. Duncan, L., Alper, S., Arigoni, F., Losick, R. & Stragier, P. Activation of cell-specific transcription by a serine phosphatase at the site of asymmetric division. Science 270, 641–644 (1995)

    ADS  CAS  Article  Google Scholar 

  4. Lord, M., Barillà, D. & Yudkin, M. D. Replacement of vegetative σA by sporulation-specific σF as a component of the RNA polymerase holoenzyme in sporulating Bacillus subtilis. J. Bacteriol. 181, 2346–2350 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Diederich, B. et al. Role of interactions between SpoIIAA and SpoIIAB in regulating cell-specific transcription factor σF of Bacillus subtilis. Genes Dev. 8, 2653–2663 (1994)

    CAS  Article  Google Scholar 

  6. Clarkson, J., Shu, J.-C., Harris, D. A., Campbell, I. D. & Yudkin, M. D. Fluorescence and kinetic analysis of the SpoIIAB phosphorylation reaction, a key regulator of sporulation in Bacillus subtilis. Biochemistry 43, 3120–3128 (2004)

    CAS  Article  Google Scholar 

  7. Clarkson, J., Campbell, I. D. & Yudkin, M. D. Physical evidence for the induced release of the Bacillus subtilis transcription factor, σF, from its inhibitory complex. J. Mol. Biol. 340, 203–209 (2004)

    CAS  Article  Google Scholar 

  8. Clarkson, J., Campbell, I. D. & Yudkin, M. D. Efficient regulation of σF, the first sporulation-specific sigma factor in B. subtilis. J. Mol. Biol. 342, 1187–1195 (2004)

    CAS  Article  Google Scholar 

  9. Shu, J.-C., Clarkson, J. & Yudkin, M. D. Studies of SpoIIAB mutant proteins elucidate the mechanisms that regulate the developmental transcription factor σF in Bacillus subtilis. Biochem. J. 384, 169–178 (2004)

    CAS  Article  Google Scholar 

  10. Garsin, D. A., Duncan, L., Paskowitz, D. M. & Losick, R. The kinase activity of the antisigma factor SpoIIAB is required for activation as well as inhibition of transcription factor σF during sporulation in Bacillus subtilis. J. Mol. Biol. 284, 569–578 (1998)

    CAS  Article  Google Scholar 

  11. Lee, C.-S., Lucet, I. & Yudkin, M. D. Fate of the SpoIIAB*-ADP liberated after SpoIIAB phosphorylates SpoIIAA of Bacillus subtilis. J. Bacteriol. 182, 6250–6253 (2000)

    CAS  Article  Google Scholar 

  12. Lucet, I., Borriss, R. & Yudkin, M. D. Purification, kinetic properties, and intracellular concentration of SpoIIE, an integral membrane protein that regulates sporulation in Bacillus subtilis. J. Bacteriol. 181, 3242–3245 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Schroeter, R., Schlisio, S., Lucet, I., Yudkin, M. D. & Borriss, R. The Bacillus subtilis regulator protein SpoIIE shares functional and structural similarities with eukaryotic protein phosphatases 2C. FEMS Microbiol. Lett. 174, 117–123 (1999)

    CAS  Article  Google Scholar 

  14. Eisenstadt, E., Fisher, S., Der, C. L. & Silver, S. Manganese transport in Bacillus subtilis W23 during growth and sporulation. J. Bacteriol. 113, 1363–1372 (1973)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Magnin, T., Lord, M. & Yudkin, M. D. Contribution of partner switching and SpoIIAA cycling to regulation of σF activity in sporulating Bacillus subtilis. J. Bacteriol. 179, 3922–3927 (1997)

    CAS  Article  Google Scholar 

  16. Fujita, M. & Sadaie, Y. Rapid isolation of RNA polymerase from sporulating cells of Bacillus subtilis. Gene 221, 185–190 (1998)

    CAS  Article  Google Scholar 

  17. Kaern, M., Elston, T. C., Blake, W. J. & Collins, J. J. Stochasticity in gene expression: from theories to phenotypes. Nature Rev. Genet. 6, 451–464 (2005)

    CAS  Article  Google Scholar 

  18. Frandsen, N., Barák, I., Karmazyn-Campelli, C. & Stragier, P. Transient gene asymmetry during sporulation and establishment of cell specificity in Bacillus subtilis. Genes Dev. 13, 394–399 (1999)

    CAS  Article  Google Scholar 

  19. Dworkin, J. & Losick, R. Differential gene expression governed by chromosomal spatial asymmetry. Cell 107, 339–346 (2001)

    CAS  Article  Google Scholar 

  20. Pan, Q., Garsin, D. A. & Losick, R. Self-reinforcing activation of a cell-specific transcription factor by proteolysis of an anti-sigma factor in Bacillus subtilis. Mol. Cell 8, 873–883 (2001)

    CAS  Article  Google Scholar 

  21. Carniol, K., Eichenberger, P. & Losick, R. A threshold mechanism governing activation of the developmental regulatory protein σF in Bacillus subtilis. J. Biol. Chem. 279, 14860–14870 (2004)

    CAS  Article  Google Scholar 

  22. King, N., Dreesen, O., Stragier, P., Pogliano, K. & Losick, R. Septation, dephosphorylation, and the activation of σF during sporulation in Bacillus subtilis. Genes Dev. 13, 1156–1167 (1999)

    CAS  Article  Google Scholar 

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We thank J.-C. Shu for providing unpublished SPR and AA phosphorylation data. This work was supported by the BBSRC UK. D.I. is a Junior Research Fellow at St John's College, Oxford, and is supported by a EPSRC DTA studentship. I.D.C. acknowledges financial support from the Wellcome Trust and the NIH-funded Cell Migration Consortium. Author Contributions D.I. developed the model and conducted the simulations. J.C. performed the experiments and all the authors contributed to the concepts and writing of the paper.

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Correspondence to Dagmar Iber or Michael D. Yudkin.

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Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains details on the derivation of the mathematical model and of parameter values and a discussion of the wider relevance of the model. The also contains Supplementary Figures 1–12 and Supplementary Tables 1–3. (PDF 762 kb)

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Iber, D., Clarkson, J., Yudkin, M. et al. The mechanism of cell differentiation in Bacillus subtilis. Nature 441, 371–374 (2006).

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