Our goal is to determine how multiple regulatory mechanisms are linked together to form a system that controls polar morphogenesis and cell cycle progression in Caulobacter crescentus. The completion of the annotated genome sequence of 3767 genes, ease of synchrony and genetic manipulation, and full genome microarray analysis have allowed us to explore the global regulatory network that controls a bacterial cell cycle. Temporally regulated transcription, signal transduction mediated by the two component family of proteins, and temporally controlled proteolytic events all contribute to the control of the Caulobacter cell cycle. In addition, we discovered that regulatory proteins that control the cell cycle and asymmetry at cell division are dynamically localized to cell poles. We will now determine why and how these proteins are dynamically positioned to specific sites in the cell. Temporally controlled clearance from the cell of the components of the polar pili, flagellum, and chemotaxis complex, and the regulatory proteins that regulate their biogenesis, is critical for the establishment of asymmetry. We will determine the mechanisms that are used to control the proteolysis of both structural and regulatory proteins at critical times in the cell cycle. Finally, we have found that of 550 genes whose transcription is regulated during the cell cycle, 25 percent are controlled by the CtrA response regulator. We will now identify the global regulators that control temporally expressed genes that are independent of CtrA control. We will also identify the groups of genes that are controlled by 5 new regulatory proteins that are themselves directly controlled by CtrA at specific times in the cell cycle in an attempt to construct a serially connected network that integrates the genetic circuitry. The proposed experiments will explore individual regulatory mechanisms in depth while determining how they form a three-dimensional network for the control of the cell cycle. ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Microbial Physiology and Genetics Subcommittee 2 (MBC)
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Zatz, Marion M
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Mann, Thomas H; Shapiro, Lucy (2018) Integration of cell cycle signals by multi-PAS domain kinases. Proc Natl Acad Sci U S A 115:E7166-E7173
Perez, Adam M; Mann, Thomas H; Lasker, Keren et al. (2017) A Localized Complex of Two Protein Oligomers Controls the Orientation of Cell Polarity. MBio 8:
Schrader, Jared M; Li, Gene-Wei; Childers, W Seth et al. (2016) Dynamic translation regulation in Caulobacter cell cycle control. Proc Natl Acad Sci U S A 113:E6859-E6867
Lasker, Keren; Schrader, Jared M; Men, Yifei et al. (2016) CauloBrowser: A systems biology resource for Caulobacter crescentus. Nucleic Acids Res 44:D640-5
Ricci, Dante P; Melfi, Michael D; Lasker, Keren et al. (2016) Cell cycle progression in Caulobacter requires a nucleoid-associated protein with high AT sequence recognition. Proc Natl Acad Sci U S A 113:E5952-E5961
Mann, Thomas H; Seth Childers, W; Blair, Jimmy A et al. (2016) A cell cycle kinase with tandem sensory PAS domains integrates cell fate cues. Nat Commun 7:11454
Lasker, Keren; Mann, Thomas H; Shapiro, Lucy (2016) An intracellular compass spatially coordinates cell cycle modules in Caulobacter crescentus. Curr Opin Microbiol 33:131-139
Schrader, Jared M; Shapiro, Lucy (2015) Synchronization of Caulobacter crescentus for investigation of the bacterial cell cycle. J Vis Exp :
Zhou, Bo; Schrader, Jared M; Kalogeraki, Virginia S et al. (2015) The global regulatory architecture of transcription during the Caulobacter cell cycle. PLoS Genet 11:e1004831
Ptacin, Jerod L; Gahlmann, Andreas; Bowman, Grant R et al. (2014) Bacterial scaffold directs pole-specific centromere segregation. Proc Natl Acad Sci U S A 111:E2046-55

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