Penelope Higgs (fm0291)

4115 Biological Sciences Building

The research interests in our group include those which have fascinated developmental biologists for ages. What are regulatory mechanisms which segregate cells into distinct fates? What molecular mechanisms drive cell morphogenesis? How is programmed cell death induced and mediated? What mechanisms induce and mediate quiescent/persistent states? What signaling strategies are employed to regulate complex behavior? How are individual regulatory pathways integrated into a signaling network?

Our model organism, Myxococcus xanthus, is a bacterium renowned for its fascinating multicellular behaviors. 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, M. xanthus instead initiates 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 bioinformatic 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.

Current projects

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 systems 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.

Spore morphogenesis

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) remodeling 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 signaling pathways. We are interested in characterizing these unusual signaling proteins and understanding how signals and signaling proteins are integrated to control the molecular processes necessary for the developmental program in M. xanthus. 

Higgs lab mentoring statement

How does one become an excellent scientist? An excellent scientist is well-rounded. Clearly, a scientist must have the ability to design, implement, interpret and troubleshoot experiments. Equally importantly, a scientist should have excellent communication skills (written and oral), be an effective leader and a good team player; be organized and methodical, but creative; be rigorous and ethical, be scientifically curious and contribute to education of the community.

Some of these skills come from classes and experience “at the bench”. Most of these skills are developed by mentoring from your PI, your thesis committee and the scientific community. In the Higgs lab, mentoring occurs over the entire period of training and is very much individualized to each student. However, as a general guideline, each student is trained with a hands on approach during the first one-two years to develop fundamental skills. Students are then encouraged to “take charge of the project” by outlining the next steps to bring to me for discussion. In the final stage, students typically develop their own follow-up project from start to completion.

Presentation skills: During all phases of graduate student training, I mentor students to develop presentation skills. Students are required to attend Biological Sciences departmental seminars and attend and present in the Departmental Research retreat, Chemistry-Biology Interface seminars, Molecular Biology and Biotechnology Division seminars, Wayne State graduate/postdoc symposium and local Michigan Branch of American Society for Microbiology conferences. Students are highly encouraged to present their research in international conferences such as the International Conference on the Myxobacteria, Bacterial Locomotion and Signal Transduction (BLAST), Gordon Research Conference on Signal Transduction in Microorganisms, or Molecular Genetics of Bacteria and Phages, among others. In all of these venues, students are encouraged to ask questions of speakers and interact with scientists outside of their own group.

Writing skills: Development of writing skills occurs during courses and especially for PhD students in preparation for their candidacy exam. Each student is expected to write a draft of all of their meeting abstracts and their manuscripts. Learning to write scientific manuscripts is a long process and involves several iterations. Students are also encouraged to proof-read manuscripts and/or grant proposals of their lab mates.

Leadership and team skills: Students are encouraged to train and mentor undergraduate and junior graduate students. Importantly, students are expected to contribute to the scientific community by taking leadership roles in the Biological Sciences Graduate student association, contributing to department committees and in organization of the Department Retreats. Students are also encouraged to participate in community science outreach, including in the WSU STEM day and high school outreach. Students are encouraged to be active in the Biological Sciences Graduate Student Association and contribute to departmental committee student service. I support and encourage opportunities to explore diverse careers in science, including participation in the WSU Broadening Experience in Scientific Training (BEST) program.

On-going research support

• NSF grant: IOS- 165609 Higgs (PI) 02/01/17-01/31/25* no cost extension
• CAREER: A CURE for Signaling Networks in Multicellular Bacteria
• Role: PI

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
• Role: PI 

• McLaughlin M, Higgs PI. Mutation of self-binding sites in the promoter of the MrpC transcriptional regulator leads to asynchronous Myxococcus xanthus development. Front Microbiol. 2023 Nov 23;14:1293966. doi: 10.3389/fmicb.2023.1293966. PMID: 38075919; PMCID: PMC10701913.
• Muñoz-Dorado J, Moraleda-Muñoz A, Marcos-Torres FJ, Contreras-Moreno FJ, Martin-Cuadrado AB, Schrader JM, Higgs PI, Pérez J.Transcriptome dynamics of the Myxococcus xanthus multicellular developmental program. Elife. 2019;8:e50374. Published 2019 Oct 14. doi:10.7554/eLife.50374
• McLaughlin PT, Higgs PI. A negative autoregulation network motif is required for synchronized Myxococcus xanthus development. bioRxiv 738716; doi: https://doi.org/10.1101/738716
• Feeley BE, Bhardwaj V, McLaughlin PT, Diggs S, Blaha GM, and P.I. Higgs. An amino-terminal threonine/serine motif is necessary for activity of the Crp/Fnr homolog, MrpC, and for Myxococcus xanthus developmental robustness. (2019) Molecular Microbiology doi: 10.1111/mmi.14378
• 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.  (2019) Journal of Bacteriology doi: 10.1128/JB.00561-18
• 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. 187:8191-8195