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4115 Biological Sciences Building
Research Interest/Area of Expertise
The research interests in our group include those which have fascinated development biologists for ages. What are regulatory mechanisms which segregate cells into distinct developmental fates? What molecular mechanisms drive cell morphogenesis? How is programmed cell death induced and mediated? What mechanisms induce and mediate quiescent / persistent states? What signalling strategies are employed to regulate complex behaviour? How are individual regulatory pathways integrated into to signalling network?
Our model organism, Myxococcus xanthus, is a bacterium renowned for its fascinating multicellular behaviours. During growth, swarms of M. xanthus feed on prey microorganisms this is a cooperative process involving collective secretion of antibiotics and degradative enzymes which paralyze, lyse, and digest prey. When nutrients become limiting, groups of M. xanthus initiate a multicellular developmental program in which cells segregate into distinct fates. Some cells are directed to migrate into mounds of approximately 100,000 cells and then differentiate into environmentally resistant spores. Alternate cell fates include programmed cell death, formation of a persister-like state and production of inert, extracellular matrix-encased aggregates. These processes are tightly controlled by a series of temporally regulated extracellular and intracellular signals that must be coordinated and integrated to ensure proper development.
M. xanthus is readily cultivated, and an array of genetic, cell biology, and &ldquoomic&rdquo tools are available. Complete genome sequences of M. xanthus and several of its relatives are available for comparative genomic analyses. My research group applies genetic, biochemical, cell biology, transcriptomic, and bioinformatic approaches to address our research goals.
Cell fate segregation
Our current interests involve defining the regulatory mechanisms which drive segregation of M. xanthus cells into distinct developmental fates including formation of spore-filled fruiting bodies, programmed cell death, or a persister like state termed peripheral rods. We have defined the proportion and cells which segregate into each cell fate and have developed methods to isolate developmental subpopulations enriched for distinct cell fates. We are interested in identifying genes or proteins which can serve as markers for the distinct cell fates for single cell analysis. Simultaneously, we have identified a series of mutants in which cell fate segregation is perturbed and have determined that these mutants affect the accumulation patterns of important developmental regulators. We are currently investigating how these tems control accumulation of the developmental regulators at a molecular level. Our long term goal is to define and model the integrated signalling network which controls cell fate segregation during M. xanthus development.
Another focus in our group is investigation of the unique spore formation process in M. xanthus, one of the rare Gram negative spore-forming bacteria. Unlike spores produced from an unequal septation event in Gram positive species (such as Bacillus subtilus), M. xanthus spores are produced by rearranging the 7 x 0.5 µm rod-shaped cell into a ~1.5 µm in diameter spherical spore in a largely undefined process. We have previously performed global transcriptome analysis (microarrays) on sporulating cells to identify genes which are necessary for sporulation and are currently focusing on a class of these genes which, when mutated, lead to severe morphological perturbations after induction of sporulation. Since these genes all encode homologs of proteins involved in polysaccharide biosynthesis, we hypothesized they may be perturbed in production of the carbohydrate-rich spore coat. So far, we have characterized protein machinery necessary to deposit spore coat material on the cell surface (Exo) as well as protein machinery which is necessary to arrange the spore coat material into a rigid compact spore coat (Nfs). We are currently biochemically characterizing these two protein machineries and analyzing the chemical properties of the spore coat material.
We are also interested in the mechanisms driving rearrangement of the rod-shaped vegetative cell into a spherical spore. We have shown that the cell cytoskeletal protein, MreB, is necessary for this process and have begun to identify and characterize proteins involved in the cell wall (peptidoglycan) remodelling and degradation during the sporulation process.
Signal transduction mechanisms
Analysis of the M. xanthus genome indicates that this organism is amazingly rich in signal transduction proteins, including approximately 280 proteins of the two-component signal transduction family and nearly 100 eukaryotic-like serine/threonine kinase homologs. Interestingly, the genetic organization and domain architecture of many of these proteins is unusual suggesting these proteins participate in non-canonical signalling pathways. We are interested in characterizing these unusual signalling proteins and understanding how signals and signalling proteins are integrated to control the molecular processes necessary for the developmental program in M. xanthus. So far, we have defined novel signalling flows in the Red four-component histidine aspartate phosphorelay tem and the inter/intra phosphotransfer mechanism of the EspAC hybrid histidine kinases.
Education – Degrees, Licenses, Certifications
- Ph.D. Washington State University (2001)
- B.Sc. Washington State University (1994)
Awards and Grants
On-going research support
NSF grant: IOS- 165609 Higgs (PI) 02/01/17-01/31/22
CAREER: A CURE for Signaling Networks in Multicellular Bacteria
Completed research support
DFG grant: HI 1593/2-1 Higgs (PI) 12/12/12-06/30/16
Sporulation in the Gram negative bacterium, Myxococcus xanthus
Glaser, M., and P.I. Higgs. The orphan hybrid histidine protein kinase, SinK, acts as a signal integrator to fine-tune multicellular behavior in Myxococcus xanthus. in press
McLaughlin, P.T., Bhardwaj, V., Feeley, B.E., and P.I. Higgs. MrpC, a CRP/Fnr homolog, functions as a negative autoregulator to control the Myxococcus xanthus multicellular developmental program. (2018) Molecular Microbiology 109(2):245
Prüβ BM, Liu J, Higgs PI, Thompson LK. Lessons in Fundamental Mechanisms and Diverse Adaptations from the 2015 Bacterial Locomotion and Signal Transduction Meeting. (2015) Journal of Bacteriology 197:3028-40
Holkenbrink C, Hoiczyk E, Kahnt J, and P.I. Higgs. Synthesis and assembly of a novel glycan layer in Myxococcus xanthus spores. (2014). Journal of Biological Chemistry. 289:32364-78
Higgs. P.I., Hartzell, P.L., Holkenbrink. C., and E. Hoiczyk. Myxococcus xanthus vegetative and developmental cell heterogeneity. (2014). In Myxobacteria: Genomics and Molecular Biology. Yang, Z. and Higgs, P.I. (ed.) Horizon Scientific Press, Norfolk, UK. pp. 51-71
Muñoz-Dorado, J., Higgs, P.I., and M. Elías-Arnanz. Abundance and complexity of signaling mechanisms in the mycobacteria. (2014). In Myxobacteria: Genomics and Molecular Biology. Yang, Z. and Higgs, P.I. (ed.) Horizon Scientific Press, Norfolk, UK. pp. 127-149
Schramm, A., Lee, B. and P.I. Higgs. Intra- and interprotein phosphorylation between two-hybrid histidine kinases controls Myxococcus xanthus developmental progression. (2012) Journal of Biological Chemistry. 287:25060-72
Lee, B., Holkenbrink, C., Treuner-Lange, A., and P.I. Higgs. Myxococcus xanthus developmental cell fate production: heterogeneous accumulation of developmental regulatory proteins and reexamination of the role of MazF in developmental lysis. (2012) Journal of Bacteriology.194:3058-68.
Müller, F., Schink, C., Hoiczyk, E., Cserti, E., and P.I. Higgs. Spore formation in Myxococcus xanthus is tied to cytoskeleton functions and polysaccharide spore coat deposition. (2012) Molecular Microbiology. 83:486-505
Lee, B., Mann, P., Grover, V., Treuner-Lange, A., Kahnt, J., and P.I. Higgs. The Myxococcus xanthus spore cuticula Protein C is a fragment of FibA, an extracellular metalloprotease produced exclusively in aggregated cells. (2011) PLoS One. 6(12):e28968
Müller, F., Treuner-Lange, A., Heider, J., Huntley, S.M., and P.I. Higgs. Global transcriptome analysis of spore formation in Myxococcus xanthus reveals a locus necessary for cell differentiation. (2010) BMC Genomics. 11:264.
Lee, B., Schramm, A., Jagadeesan S., and P.I. Higgs. Two-component tems and regulation of developmental progression in Myxococcus xanthus. (2010) Methods in Enzymology Volume 471, Chapter 14, Pages 253-278
Jagadeesan, S., Mann, P., Schink, C.W., and P.I. Higgs. A novel "four-component" two-component signal transduction mechanism regulates developmental progression in Myxococcus xanthus. (2009) Journal of Biological Chemistry. 284:21435-45.
Higgs, P.I., Jagadeesan, S., Mann, P., and D.R. Zusman. EspA, an orphan histidine protein kinase, regulates the timing of expression of key developmental proteins of Myxococcus xanthus. (2008) Journal of Bacteriology. 190:4416-26.
Article highlighted in: Kroos L. Bacterial development in the fast lane. (2008) Journal of Bacteriology. 190:4373-6
P.I. Higgs, and J.P. Merlie, Jr. Myxococcus xanthus: Cultivation, Motility, and Development. In Myxobacteria: Multicellularity and Differentiation. Whitworth, D. (ed.) (2008) ASM, Press, Washington D.C.
Stein, E.A., Cho, K., Higgs, P.I., and D.R. Zusman. Two Ser/Thr protein kinases essential for efficient aggregation and spore morphogenesis in Myxococcus xanthus. (2006) Molecular Microbiology. 60:1414&ndash1431
Higgs, P.I., Cho, K., Whitworth, D.E., Evans, L.S., and D.R. Zusman Four Unusual Two-Component Signal Transduction Homologs, RedC to RedF, Are Necessary for Timely Development in Myxococcus xanthus. (2005) Journal of Bacteriology. 187:8191&ndash8195
BIO 4370 Microbial Communities in Health and the Environment
BIO 5330 Principals and Applications of Biotechnology 3 Credit hrs
BIO 2200 W18 Introduction to Microbiology 5 Credit hrs
BIO 4350 F17 Bacterial Molecular Genetics Lab 3 Credit hrs
BIO 6120 W17 Molecular biology lab 4 Credit hrs
BIO 5060 F16 Special Topics: Microbial communities in health and the environment 3 Credit hrs
BIO 8995 W16 Graduate Seminar 1 Credit hr
BIO 8000 W16 Special Topics: Signal transduction mechanisms 3 Credit hrs