The fundamental basis for the generation of cellular diversity in all organisms is the asymmetric deployment of structural and regulatory proteins to the cell poles prior to cell division and the consequent differential readout of the genome in the two daughter cells. The bacterium Caulobacter crescentus provides an elegant system in which to decipher the complete molecular circuitry that controls the asymmetry that underlies cell differentiation. As Caulobacter moves through its cell cycle, cell differentiation is accompanied by the polar localization of distinct complements of phospho-signaling proteins. The goals of our research program turn on three important questions: 1- How does a polar matrix nanodomain function to dynamically re-wire polar phosphosignaling pathways to drive cell differentiation and asymmetric cell division? We are approaching this question through reconstitution of the polar environment using liposomes and microfabricated solid substrates, three dimensional superresolution imaging modalities and single molecule tracking in living cells, and the creation of optogenetic mutants that enable instantaneous light-induced reconfiguration of the cell pole composition, thereby allowing us to directly observe the consequences of re-wiring a spatially-restricted signaling cascade in a living cell. 2- How do cell-type specific signaling pathways beget cell type-specific gene expression? We are defining the exquisite complexity of the complete genetic circuitry that uses both transcriptional and translation control to drive cell cyce progression culminating in daughter cells of different cell fate. 3- How does chromosome organization, replication and segregation along the long axis of the cell serve as a timer of cell cycle-regulated transcription using epigenetic mechanisms? Our goal is to integrate these spatiotemporal regulatory paradigms to establish the logic that is applicable to the dissection of asymmetry in all living systems.
We are faced with a growing infectious disease threat at the same time that we have rampant growth of resistance to all our known antibiotics. By defining the complete genetic circuitry that incorporates the 3D deployment of regulatory proteins to yield bacterial cells of different cell fate, we are uncovering novel antibiotic targets that has led to the design and development of a new class of antibiotics.
| 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 |
| Bayas, Camille A; Wang, Jiarui; Lee, Marissa K et al. (2018) Spatial organization and dynamics of RNase E and ribosomes in Caulobacter crescentus. Proc Natl Acad Sci U S A 115:E3712-E3721 |
| Dahlberg, Peter D; Sartor, Annina M; Wang, Jiarui et al. (2018) Identification of PAmKate as a Red Photoactivatable Fluorescent Protein for Cryogenic Super-Resolution Imaging. J Am Chem Soc 140:12310-12313 |
| Herrmann, Jonathan; Jabbarpour, Fatemeh; Bargar, Paul G et al. (2017) Environmental Calcium Controls Alternate Physical States of the Caulobacter Surface Layer. Biophys J 112:1841-1851 |
| 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: |
| Saurabh, Saumya; Perez, Adam M; Comerci, Colin J et al. (2017) Super-Resolution Microscopy and Single-Protein Tracking in Live Bacteria Using a Genetically Encoded, Photostable Fluoromodule. Curr Protoc Cell Biol 75:4.32.1-4.32.22 |
| 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 |
| Saurabh, Saumya; Perez, Adam M; Comerci, Colin J et al. (2016) Super-resolution Imaging of Live Bacteria Cells Using a Genetically Directed, Highly Photostable Fluoromodule. J Am Chem Soc 138:10398-401 |
| 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 |
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