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Chance and Necessity in Development

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  • Authors: Nicolas Mirouze1, David Dubnau2
  • Editor: Patrick Eichenberger3
    Affiliations: 1: UMR1319 Micalis, Bat. Biotechnologie (440), INRA, Domaine de Vilvert, 78352 Jouy-en-Josas Cedex, France; 2: Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103; 3: New York University, New York, NY 10003
  • Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspectrum.TBS-0004-2012
  • Received 17 August 2012 Accepted 06 May 2013 Published 25 October 2013
  • David Dubnau, [email protected]
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  • Abstract:

    is an important model bacterium for the study of developmental adaptations that enhance survival in the face of fluctuating environmental challenges. These adaptations include sporulation, biofilm formation, motility, cannibalism, and competence. Remarkably, not all the cells in a given population exhibit the same response. The choice of fate by individual cells is random but is also governed by complex signal transduction pathways and cross talk mechanisms that reinforce decisions once made. The interplay of stochastic and deterministic mechanisms governing the selection of developmental fate on the single-cell level is discussed in this article.

  • Citation: Mirouze N, Dubnau D. 2013. Chance and Necessity in Development. Microbiol Spectrum 1(1):TBS-0004-2012. doi:10.1128/microbiolspectrum.TBS-0004-2012.


1. Balazsi G, van Oudenaarden A, Collins JJ. 2011. Cellular decision making and biological noise: from microbes to mammals. Cell 144:910–925.
2. Losick R, Desplan C. 2008. Stochasticity and cell fate. Science 320:65–68.
3. Eldar A, Elowitz MB. 2010. Functional roles for noise in genetic circuits. Nature 467:167–173.
4. Raj A, van Oudenaarden A. 2008. Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135:216–226.
5. Elowitz MB, Levine AJ, Siggia ED, Swain PS. 2002. Stochastic gene expression in a single cell. Science 297:1183–1186.
6. Swain PS, Elowitz MB, Siggia ED. 2002. Intrinsic and extrinsic contributions to stochasticity in gene expression. Proc Natl Acad Sci USA 99:12795–12800.
7. Taniguchi Y, Choi PJ, Li GW, Chen H, Babu M, Hearn J, Emili A, Xie XS. 2010. Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science 329:533–538.
8. Hamoen LW, Smits WK, de Jong A, Holsappel S, Kuipers OP. 2002. Improving the predictive value of the competence transcription factor (ComK) binding site in Bacillus subtilis using a genomic approach. Nucleic Acids Res 30:5517–5528.
9. Ogura M, Yamaguchi H, Kobayashi K, Ogasawara N, Fujita Y, Tanaka T. 2002. Whole-genome analysis of genes regulated by the Bacillus subtilis competence transcription factor ComK. J Bacteriol 184:2344–2351.
10. Berka RM, Hahn J, Albano M, Draskovic I, Persuh M, Cui X, Sloma A, Widner W, Dubnau D. 2002. Microarray analysis of the Bacillus subtilis K-state: genome-wide expression changes dependent on ComK. Mol Microbiol 43:1331–1345.
11. Lemon KP, Earl AM, Vlamakis HC, Aguilar C, Kolter R. 2008. Biofilm development with an emphasis on Bacillus subtilis. Curr Top Microbiol Immunol 322:1–16.
12. McLoon AL, Guttenplan SB, Kearns DB, Kolter R, Losick R. 2011. Tracing the domestication of a biofilm-forming bacterium. J Bacteriol 193:2027–2034.
13. Burbulys D, Trach KA, Hoch JA. 1991. Initiation of sporulation in B. subtilis is controlled by a multicomponent phosphorelay. Cell 64:545–552.
14. Chastanet A, Vitkup D, Yuan GC, Norman TM, Liu JS, Losick RM. 2010. Broadly heterogeneous activation of the master regulator for sporulation in Bacillus subtilis. Proc Natl Acad Sci USA 107:8486–8491.
15. Fujita M, Gonzalez-Pastor JE, Losick R. 2005. High- and low-threshold genes in the Spo0A regulon of Bacillus subtilis. J Bacteriol 187:1357–1368.
16. Fujita M, Losick R. 2005. Evidence that entry into sporulation in Bacillus subtilis is governed by a gradual increase in the level and activity of the master regulator Spo0A. Genes Dev 19:2236–2244.
17. de Jong IG, Veening JW, Kuipers OP. 2010. Heterochronic phosphorelay gene expression as a source of heterogeneity in Bacillus subtilis spore formation. J Bacteriol 192:2053–2067.
18. van Sinderen D, Luttinger A, Kong L, Dubnau D, Venema G, Hamoen L. 1995. comK encodes the competence transcription factor, the key regulatory protein for competence development in Bacillus subtilis. Mol Microbiol 15:455–462.
19. Turgay K, Hahn J, Burghoorn J, Dubnau D. 1998. Competence in Bacillus subtilis is controlled by regulated proteolysis of a transcription factor. EMBO J 17:6730–6738.
20. Serror P, Sonenshein AL. 1996. CodY is required for nutritional repression of Bacillus subtilis genetic competence. J Bacteriol 178:5910–5915.
21. Hamoen LW, Kausche D, Marahiel MA, van Sinderen D, Venema G, Serror P. 2003. The Bacillus subtilis transition state regulator AbrB binds to the −35 promoter region of comK. FEMS Microbiol Lett 218:299–304.
22. Hoa TT, Tortosa P, Albano M, Dubnau D. 2002. Rok (YkuW) regulates genetic competence in Bacillus subtilis by directly repressing comK. Mol Microbiol 43:15–26.
23. Haijema BJ, Hahn J, Haynes J, Dubnau D. 2001. A ComGA-dependent checkpoint limits growth during the escape from competence. Mol Microbiol 40:52–64.
24. Magnuson R, Solomon J, Grossman AD. 1994. Biochemical and genetic characterization of a competence pheromone from B. subtilis. Cell 77:207–216.
25. Prepiak P, Dubnau D. 2007. A peptide signal for adapter protein-mediated degradation by the AAA+ protease ClpCP. Mol Cell 26:639–647.
26. Smits WK, Eschevins CC, Susanna KA, Bron S, Kuipers OP, Hamoen LW. 2005. Stripping Bacillus: ComK auto-stimulation is responsible for the bistable response in competence development. Mol Microbiol 56:604–614.
27. Maamar H, Dubnau D. 2005. Bistability in the Bacillus subtilis K-state (competence) system requires a positive feedback loop. Mol Microbiol 56:615–624.
28. Leisner M, Stingl K, Radler JO, Maier B. 2007. Basal expression rate of comK sets a ‘switching-window’ into the K-state of Bacillus subtilis. Mol Microbiol 63:1806–1816.
29. Maamar H, Raj A, Dubnau D. 2007. Noise in gene expression determines cell fate in Bacillus subtilis. Science 317:526–529.
30. Cagatay T, Turcotte M, Elowitz MB, Garcia-Ojalvo J, Süel GM. 2009. Architecture-dependent noise discriminates functionally analogous differentiation circuits. Cell 139:512–522.
31. Süel GM, Garcia-Ojalvo J, Liberman LM, Elowitz MB. 2006. An excitable gene regulatory circuit induces transient cellular differentiation. Nature 440:545–550.
32. Süel GM, Kulkarni RP, Dworkin J, Garcia-Ojalvo J, Elowitz MB. 2007. Tunability and noise dependence in differentiation dynamics. Science 315:1716–1719.
33. Albano M, Hahn J, Dubnau D. 1987. Expression of competence genes in Bacillus subtilis. J Bacteriol 169:3110–3117.
34. Mirouze N, Desai Y, Raj A, Dubnau D. 2012. Spo0A∼P imposes a temporal gate for the bimodal expression of competence in Bacillus subtilis. PLoS Genet 8:e1002586.
35. Chai Y, Norman T, Kolter R, Losick R. 2011. Evidence that metabolism and chromosome copy number control mutually exclusive cell fates in Bacillus subtilis. EMBO J 30:1402–1413.
36. Sen S, Garcia-Ojalvo J, Elowitz MB. 2011. Dynamical consequences of bandpass feedback loops in a bacterial phosphorelay. PLoS One 6:e25102.
37. Barker MM, Gaal T, Gourse RL. 2001. Mechanism of regulation of transcription initiation by ppGpp. II. Models for positive control based on properties of RNAP mutants and competition for RNAP. J Mol Biol 305:689–702.
38. Zhou YN, Jin DJ. 1998. The rpoB mutants destabilizing initiation complexes at stringently controlled promoters behave like “stringent” RNA polymerases in Escherichia coli. Proc Natl Acad Sci U S A 95:2908–2913.
39. Mirouze N, Prepiak P, Dubnau D. 2011. Fluctuations in spo0A transcription control rare developmental transitions in Bacillus subtilis. PLoS Genet 7:e1002048.
40. Hahn J, Kong L, Dubnau D. 1994. The regulation of competence transcription factor synthesis constitutes a critical control point in the regulation of competence in Bacillus subtilis. J Bacteriol 176:5753–5761.
41. Barkai N, Leibler S. 2000. Circadian clocks limited by noise. Nature 403:267–268.
42. Kearns DB, Losick R. 2005. Cell population heterogeneity during growth of Bacillus subtilis. Genes Dev 19:3083–3094.
43. Chai Y, Norman T, Kolter R, Losick R. 2010. An epigenetic switch governing daughter cell separation in Bacillus subtilis. Genes Dev 24:754–765.
44. Berg HC. 1983. Random Walks in Biology. Princeton University Press, Princeton, NJ.
45. Bai U, Mandic-Mulec I, Smith I. 1993. SinI modulates the activity of SinR, a developmental switch protein of Bacillus subtilis, by protein-protein interaction. Genes Dev 7:139–148.
46. Chu F, Kearns DB, McLoon A, Chai Y, Kolter R, Losick R. 2008. A novel regulatory protein governing biofilm formation in Bacillus subtilis. Mol Microbiol 68:1117–1127.
47. Gardner TS, Cantor CR, Collins JJ. 2000. Construction of a genetic toggle switch in Escherichia coli. Nature 403:339–342.
48. Oppenheim AB, Kobiler O, Stavans J, Court DL, Adhya S. 2005. Switches in bacteriophage lambda development. Annu Rev Genet 39:409–429.
49. Castilla-Llorente V, Salas M, Meijer WJ. 2008. kinC/D-mediated heterogeneous expression of spo0A during logarithmical growth in Bacillus subtilis is responsible for partial suppression of phi 29 development. Mol Microbiol 68:1406–1417.
50. Cozy LM, Kearns DB. 2010. Gene position in a long operon governs motility development in Bacillus subtilis. Mol Microbiol 76:273–285.
51. Cozy LM, Phillips A, Calvo RA, Bate A, Hsueh Y-H, Bonneau R, Eichenberger P, Kearns DB. 2012. SlrA/SlrR/SinR inhibits motility gene expression upstream of a hypersensitive and hysteric switch at the level of sD in Bacillus subtilis. Mol Microbiol 83:1210–1228.
52. Kobayashi K. 2008. SlrR/SlrA controls the initiation of biofilm formation in Bacillus subtilis. Mol Microbiol 69:1399–1410.
53. Chai Y, Kolter R, Losick R. 2009. Paralogous antirepressors acting on the master regulator for biofilm formation in Bacillus subtilis. Mol Microbiol 74:876–887.
54. Patrick JE, Kearns DB. 2012. Swarming motility and the control of master regulators of flagellar biosynthesis. Mol Microbiol 83:14–23.
55. Werhane H, Lopez P, Mendel M, Zimmer M, Ordal GW, Marquez-Magana LM. 2004. The last gene of the fla/ che operon in Bacillus subtilis, ylxL, is required for maximal σD function. J Bacteriol 186:4025–4029.
56. Calvio C, Celandroni F, Ghelardi E, Amati G, Salvetti S, Ceciliani F, Galizzi A, Senesi S. 2005. Swarming differentiation and swimming motility in Bacillus subtilis are controlled by swrA, a newly identified dicistronic operon. J Bacteriol 187:5356–5366.
57. Hsueh YH, Cozy LM, Sham LT, Calvo RA, Gutu AD, Winkler ME, Kearns DB. 2011. DegU-phosphate activates expression of the anti-sigma factor FlgM in Bacillus subtilis. Mol Microbiol 81:1092–1108.
58. Higgins D, Dworkin J. Recent progress in Bacillus subtilis sporulation. FEMS Microbiol Rev 36:131–148.
59. Hoch JA. 1993. spoO genes, the phosphorelay, and the initiation of sporulation, p 747–755. In Sonenshein AL, Hoch JA, Losick R (ed.), Bacillus subtilis and Other Gram-Positive Bacteria: Biochemistry, Physiology, and Molecular Genetics. American Society for Microbiology, Washington, DC.
60. Aguilar C, Vlamakis H, Guzman A, Losick R, Kolter R. 2010. KinD is a checkpoint protein linking spore formation to extracellular-matrix production in Bacillus subtilis biofilms. mBio 1(1) :e00035-10.
61. Schaeffer P, Millet J, Aubert J-P. 1965. Catabolic repression of bacterial sporulation. Proc Natl Acad Sci USA 54:704–711.
62. Sterlini JM, Mandelstam J. 1969. Commitment to sporulation in Bacillus subtilis and its relationship to development of actinomycin resistance. Biochem J 113:29–37.
63. Perego M, Hanstein C, Welsh KM, Djavakhishvili T, Glaser P, Hoch JA. 1994. Multiple protein-aspartate phosphatases provide a mechanism for the integration of diverse signals in the control of development in B. subtilis. Cell 79:1047–1055.
64. Perego M. 2001. A new family of aspartyl phosphate phosphatases targeting the sporulation transcription factor Spo0A of Bacillus subtilis. Mol Microbiol 42:133–143.
65. Burkholder WF, Kurtser I, Grossman AD. 2001. Replication initiation proteins regulate a developmental checkpoint in Bacillus subtilis. Cell 104:269–279.
66. Hosoya S, Asai K, Ogasawara N, Takeuchi M, Sato T. 2002. Mutation in yaaT leads to significant inhibition of phosphorelay during sporulation in Bacillus subtilis. J Bacteriol 184:5545–5553.
67. Tortosa P, Albano M, Dubnau D. 2000. Characterization of ylbF, a new gene involved in competence development and sporulation in Bacillus subtilis. Mol Microbiol 35:1110–1119.
68. Carabetta VJ, Tanner AW, Greco TM, Defrancesco M, Cristea IM, Dubnau D. 2013. A complex of YlbF, YmcA and YaaT regulates sporulation, competence and biofilm formation by accelerating the phosphorylation of Spo0A. Mol Microbiol 88:283–300.
69. Chung JD, Stephanopoulos G, Ireton K, Grossman AD. 1994. Gene expression in single cells of Bacillus subtilis: evidence that a threshold mechanism controls the initiation of sporulation. J Bacteriol 176:1977–1984.
70. Dubnau D, Losick R. 2006. Bistability in bacteria. Mol Microbiol 61:564–572.
71. Chastanet A, Losick R. 2011. Just-in-time control of Spo0A synthesis in Bacillus subtilis by multiple regulatory mechanisms. J Bacteriol 193:6366–6374.
72. Eswaramoorthy P, Dinh J, Duan D, Igoshin OA, Fujita M. Single-cell measurement of the levels and distributions of the phosphorelay components in a population of sporulating Bacillus subtilis cells. Microbiology 156:2294–2304.
73. Kuchina A, Espinar L, Garcia-Ojalvo J, Süel G. 2011. Reversible and noisy progression towards a commitment point enables adaptable and reliable cellular decision-making. PLoS Comp Biol 7:e1002273.
74. Duncan L, Alper S, Arigoni F, Losick R, Stragier P. 1995. Activation of cell-specific transcription by a serine phosphatase at the site of asymmetric division. Science 270:641–644.
75. Arigoni F, Pogliano K, Webb CD, Stragier P, Losick R. 1995. Localization of protein implicated in establishment of cell type to sites of asymmetric division. Science 270:637–640.
76. Narula J, Devi SN, Fujita M, Igoshin OA. 2012. Ultrasensitivity of the Bacillus subtilis sporulation decision. Proc Natl Acad Sci USA 109:E3513–E3522.
77. Eswaramoorthy P, Duan D, Dinh J, Dravis A, Devi SN, Fujita M. 2010. The threshold level of the sensor histidine kinase KinA governs entry into sporulation in Bacillus subtilis. J Bacteriol 192:3870–3882.
78. Alon U. 2007. An Introduction to Systems Biology. Design Principles of Biological Circuits. Chapman & Hall/CRC, Boca Raton, FL.
79. Dworkin J, Losick R. 2005. Developmental commitment in a bacterium. Cell 121:401–409.
80. Veening JW, Murray H, Errington J. 2009. A mechanism for cell cycle regulation of sporulation initiation in Bacillus subtilis. Genes Dev 23:1959–1970.
81. Cunningham KA, Burkholder WF. 2009. The histidine kinase inhibitor Sda binds near the site of autophosphorylation and may sterically hinder autophosphorylation and phosphotransfer to Spo0F. Mol Microbiol 71:659–677.
82. Grossman AD. 1995. Genetic networks controlling the initiation of sporulation and the development of genetic competence in Bacillus subtilis. Annu Rev Genet 29:477–508.
83. Hahn J, Roggiani M, Dubnau D. 1995. The major role of Spo0A in genetic competence is to downregulate abrB, an essential competence gene. J Bacteriol 177:3601–3605.
84. Schultz D, Wolynes PG, Ben Jacob E, Onuchic JN. 2009. Deciding fate in adverse times: sporulation and competence in Bacillus subtilis. Proc Natl Acad Sci USA 106:21027–21034.
85. Kuchina A, Espinar L, Cagatay T, Balbin AO, Zhang F, Alvarado A, Garcia-Ojalvo J, Süel GM. 2011. Temporal competition between differentiation programs determines cell fate choice. Mol Syst Biol 7:557.
86. Smits WK, Bongiorni C, Veening JW, Hamoen LW, Kuipers OP, Perego M. 2007. Temporal separation of distinct differentiation pathways by a dual specificity Rap-Phr system in Bacillus subtilis. Mol Microbiol 65:103–120.
87. Lopez D, Vlamakis H, Kolter R. 2010. Biofilms. Cold Spring Harb Perspect Biol 2:a000398.
88. Branda SS, Chu F, Kearns DB, Losick R, Kolter R. 2006. A major protein component of the Bacillus subtilis biofilm matrix. Mol Microbiol 59:1229–1238.
89. Vlamakis H, Aguilar C, Losick R, Kolter R. 2008. Control of cell fate by the formation of an architecturally complex bacterial community. Genes Dev 22:945–953.
90. Branda SS, Gonzalez-Pastor JE, Ben-Yehuda S, Losick R, Kolter R. 2001. Fruiting body formation by Bacillus subtilis. Proc Natl Acad Sci USA 98:11621–11626.
91. Chai Y, Chu F, Kolter R, Losick R. 2008. Bistability and biofilm formation in Bacillus subtilis. Mol Microbiol 67:254–263.
92. Kearns DB, Chu F, Branda SS, Kolter R, Losick R. 2005. A master regulator for biofilm formation by Bacillus subtilis. Mol Microbiol 55:739–749.
93. Chu F, Kearns DB, Branda SS, Kolter R, Losick R. 2006. Targets of the master regulator of biofilm formation in Bacillus subtilis. Mol Microbiol 59:1216–1228.
94. Blair KM, Turner L, Winkelman JT, Berg HC, Kearns DB. 2008. A molecular clutch disables flagella in the Bacillus subtilis biofilm. Science 320:1636–1638.
95. Mandic-Mulec I, Doukhan L, Smith I. 1995. The Bacillus subtilis SinR protein is a repressor of the key sporulation gene spo0A. J Bacteriol 177:4619–4627.
96. Mandic-Mulec I, Gaur N, Bai U, Smith I. 1992. Sin, a stage-specific repressor of cellular differentiation. J Bacteriol 174:3561–3569.
97. Huynh TN, Stewart V. 2011. Negative control in two-component signal transduction by transmitter phosphatase activity. Mol Microbiol 82:275–286.
98. Lopez D, Fischbach MA, Chu F, Losick R, Kolter R. 2009. Structurally diverse natural products that cause potassium leakage trigger multicellularity in Bacillus subtilis. Proc Natl Acad Sci USA 106:280–285.
99. Kobayashi K, Kuwana R, Takamatsu H. 2008. kinA mRNA is missing a stop codon in the undomesticated Bacillus subtilis strain ATCC 6051. Microbiology 154:54–63.
100. Tran L-SP, Nagai T, Itoh Y. 2000. Divergent structure of the ComQXPA quorum sensing components: molecular basis of strain-specific communication mechanism in Bacillus subtilis. Mol Microbiol 37:1159–1171.
101. Tortosa P, Logsdon L, Kraigher B, Itoh Y, Mandic-Mulec I, Dubnau D. 2001. Specificity and genetic polymorphism of the Bacillus competence quorum-sensing system. J Bacteriol 183:451–460.
102. Ansaldi M, Marolt D, Stebe T, Mandic-Mulec I, Dubnau D. 2002. Specific activation of the Bacillus quorum-sensing systems by isoprenylated pheromone variants. Mol Microbiol 44:1561–1573.
103. Stefanic P, Mandic-Mulec I. 2009. Social interactions and distribution of Bacillus subtilis pherotypes at microscale. J Bacteriol 191:1756–1764.
104. López D, Vlamakis H, Losick R, Kolter R. 2009. Paracrine signaling in a bacterium. Genes Dev 23:1631–1638.
105. Core L, Perego M. 2003. TPR-mediated interaction of RapC with ComA inhibits response regulator-DNA binding for competence development in Bacillus subtilis. Mol Microbiol 49:1509–1522.
106. Gonzalez-Pastor JE, Hobbs EC, Losick R. 2003. Cannibalism by sporulating bacteria. Science 301:510–513.
107. Lopez D, Vlamakis H, Losick R, Kolter R. 2009. Cannibalism enhances biofilm development in Bacillus subtilis. Mol Microbiol 74:609–618.
108. Kolodkin-Gal I, Romero D, Cao S, Clardy J, Kolter R, Losick R. 2010. d-Amino acids trigger biofilm disassembly. Science 328:627–629.
109. Kolodkin-Gal I, Cao S, Chai L, Bottcher T, Kolter R, Clardy J, Losick R. 2012. A self-produced trigger for biofilm disassembly that targets exopolysaccharide. Cell 149:684–692.
110. Chai Y, Kolter R, Losick R. 2010. Reversal of an epigenetic switch governing cell chaining in Bacillus subtilis by protein instability. Mol Microbiol 78:218–229.
111. Prepiak P, Defrancesco M, Spadavecchia S, Mirouze N, Albano M, Persuh M, Fujita M, Dubnau D. 2011. MecA dampens transitions to spore, biofilm exopolysaccharide and competence expression by two different mechanisms. Mol Microbiol 80:1014–1030.

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is an important model bacterium for the study of developmental adaptations that enhance survival in the face of fluctuating environmental challenges. These adaptations include sporulation, biofilm formation, motility, cannibalism, and competence. Remarkably, not all the cells in a given population exhibit the same response. The choice of fate by individual cells is random but is also governed by complex signal transduction pathways and cross talk mechanisms that reinforce decisions once made. The interplay of stochastic and deterministic mechanisms governing the selection of developmental fate on the single-cell level is discussed in this article.

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Developmental modules in B. subtilis and their major components. All of the indicated forms of development depend on 0A and on the phosphorelay that governs the phosphorylation of this transcription factor. This figure is intended to summarize many of the major interactions mentioned in the text that govern the developmental processes. It is not exhaustive, although it may be exhausting. Lines ending in perpendiculars and arrows denote negative and positive effects, respectively. Arrows associated with right-angled lines denote transcription initiation. The dotted line from the cannibalism module indicates that the release of nutrients from dead cells delays sporulation. Several kinases deliver phosphoryl groups to the phosphorelay, which results in the formation of 0A~P. Under some conditions one or more kinase can dephosphorylate 0F~P, draining phosphate from 0A~P. RapA is one of several related proteins that can also dephosphorylate 0F~P. RapC acts by preventing ComA~P from interacting with its DNA target. These Rap proteins are inhibited by cognate secreted peptides (e.g., PhrA and PhrC), which are internalized by the oligopeptide permease Spo0K. ComX is a modified and secreted peptide which activates the autophosphorylation of ComP. ComP~P donates a phosphate to ComA, and ComA~P then activates the transcription of srfA. Embedded in the srfA operon is the gene for ComS. This small protein binds to the protease complex of MecA plus ComP plus ClpC, preventing the degradation of the transcription factor ComK. ComK is then free to activate its own expression by antagonizing the repressor Rok, activating a positive autoregulatory loop. When ComK accumulates, it, in turn, activates the transcription of many downstream genes, resulting in the induction of competence (the K-state). A low level of 0A~P is also essential for competence due to its direct interaction with the comK promoter and its repression of abrB. A low to intermediate concentration of 0A~P also activates the sinI promoter. SinI antagonizes SinR, lifting the repression of several transcription units that are essential for biofilm formation, as well as the repression of slrR. SlrR binds to SinR, further derepressing the biofilm operons. The SinR-SlrR heterocomplex represses the genes for motility as well as those that encode the autolysins that separate daughter cells following division. This results in the formation of chains of sessile cells. Low concentrations of 0A~P also activate genes that encode toxins. Toxin-producing cells (cannibals) benefit by killing other cells, thus deriving nutrients. Finally, high concentrations of 0A~P activate the sporulation genes. doi:10.1128/microbiolspectrum.TBS-0004-2012.f1

Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspectrum.TBS-0004-2012
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Diagram of the uptick mechanism 34). The top portion shows a graphical representation of the Rok and 0A~P concentrations, as well as the availability of RNApol and the rate of comK basal transcription (solid black line) during the transition to stationary phase. (RNApol availability is used as a plausible stand-in for the cause of the global increase in transcription that was observed.) The peak rate of transcription coincides with T0, the time of departure from exponential growth. When the concentrations of available RNApol and of 0A~P are low (1), Rok is dominant and the rate of comK transcription is also low. As the concentration of 0A∼P increases further, Rok is antagonized at sites A1, A2, and A3 and at the same time RNApol becomes more available. As a result, the rate of comK transcription increases (2). Finally, the 0A∼P concentration reaches a level that is able to repress at R1 and R2 and comK transcription slows (3). In reality, of course, three demarcated periods of time do not exist. Note that the concentration of Rok remains constant throughout and both RNApol and 0A~P work to counteract its effects. Rok works at an unidentified site in addition to A1 to A3, shown here between A3 and R1. For simplicity, the availability of RNApol is shown as constant after T0, although the data would suggest that it varies somewhat (34). doi:10.1128/microbiolspectrum.TBS-0004-2012.f2

Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspectrum.TBS-0004-2012
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Two proposed mechanisms controlling chaining and motility (A) The epigenetic switch (43). (Adapted with permission from the authors and the publisher from Fig. 1 in reference 43.) (a) SinI sequesters SinR, relieving repression of slrR. SlrR then binds to SinR, and the resulting complex represses the autolysin and motility genes and prevents repression of the matrix genes by SinR. (b) This circuitry allows for two metastable states. In one, when SlrR is low, the autolysin and motility genes are ON and the resulting cell is motile. In the other, when the SlrR concentration is high, these genes are OFF and the cells form chains and do not swim. The central feature of the circuitry that permits this bistable switch is the double-feedback mechanism involving repression of slrR by SinR and the inactivation of SinR for matrix gene repression by binding to SlrR. If SlrR is high, repression locks the cell in the motility OFF state, and vice versa. The transition between states can be stochastic, due to fluctuations in protein concentration (noise), or deterministic, in the sense that it is a programmed developmental switch. (B) Diagram of the gene position mechanism (50, 51). SigD is the penultimate gene in the 27-kb fla-che operon. For unknown reasons, the probability that promoter-distal genes are included in the operon transcript falls off with distance. Thus, if the mean number of transcripts per cell is low, some cells will have more SigD than others, and these cells will be motile. The distance-dependent fall-off in transcript abundance is reported to be due to the action of the SinR-SlrR heterocomplex (51). doi:10.1128/microbiolspectrum.TBS-0004-2012.f3

Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspectrum.TBS-0004-2012
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Cell type determination in biofilms (60, 98, 104, 107). Pre-ComX is processed and ComX is secreted with the aid of ComQ. ComX interacts with ComP at the cell surface, resulting in the phosphorylation of ComA and the transcriptional activation of srfA. The surface-active SrfA molecule induces potassium flux in a susceptible cell, activating KinC and the formation of small amounts of 0A~P. For unknown reasons, the surfactin-producing cell itself becomes refractory to activation by surfactin. In the susceptible cell, 0A~P activates the transcription of sinI, which interacts with SinR, relieving repression of the matrix genes. For unknown reasons, matrix producers are not activated to produce surfactin. The presence of matrix downregulates the phosphatase activity of KinD, permitting the 0A~P concentration to rise further, inducing sporulation. Matrix producers also become cannibals, because their intermediate 0A~P concentration triggers toxin production. These toxins kill nonproducers, which release nutrients, delaying sporulation. As a result, matrix producers proliferate, increasing the population of eventual sporulating cells. doi:10.1128/microbiolspectrum.TBS-0004-2012.f4

Source: microbiolspec October 2013 vol. 1 no. 1 doi:10.1128/microbiolspectrum.TBS-0004-2012
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