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Department of Molecular Biology

College of Agriculture and Natural Resources

Daniel Wall

 

Daniel Wall, Ph.D.

Professor

Department of Molecular Biology
University of Wyoming
Laramie, WY 82071
Email: dwall2@uwyo.edu


Research Overview

A fundamental question in biology is how individual cells within a multicellular organism interact to coordinate diverse processes? We are interested in this question from molecular and evolutionary perspectives. To address this topic our laboratory studies the genetically tractable organism called Myxococcus xanthus. As a group, myxobacteria are highly social microbes that move, hunt and develop as coherent multicellular units. Their most notable behavior is their ability to build fruiting bodies in response to starvation. Here, thousands of individual and small groups of cells coalesce from their environment to assemble fruiting bodies wherein vegetative cells differentiate into different cell types including environmentally resistant spores (Fig. 1). In this regard our laboratory is focused on two general questions: i) At a molecular level how do cells recognition their clonemates and discriminate against non-kin? ii) How, in mechanistic and evolutionary terms, can myxobacteria transition between solitary and multicellular lifestyles?

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Fig. 1. Fruiting body development. A) A diagram of cell aggregation and fruiting body formation by M. xanthus cells (yellow) from a diverse microbial community. B) Micrograph of an actual Chondromyces crocatus fruiting body.

We propose that a partial answer to the above questions lies within a novel process that we discovered and named – outer membrane exchange (OME). Here, upon physical contact with a neighboring cell the outer membranes transiently fuse and cells exchange outer membrane proteins and lipids (Fig. 2). ME is mediated by a duo of cell surface proteins, TraA and TraB, which act as cell-cell adhesins and fusagens. The exchange or sharing of significant amounts of cellular resources within diverse microbial communities (soil) raises questions about how partner cells are identified and whether these interactions are regulated. Indeed, we found that OME is highly selective and only occurs between cells that contain identical or nearly identical TraA proteins (Fig. 3). Therefore OME involves kin recognition that is governed by genetically defined homotypic interactions between polymorphic traA alleles. Thus cells that express identical or nearly identical traA alleles form a functional recognition group, while strains with divergent TraA receptors will not exchange (Fig. 4). Molecular and phylogenetic studies further suggest that among environmental populations there are hundreds of different TraA-derived recognition or social groups (Fig. 3B).

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Fig. 2. Outer membrane exchange (OME) in myxobacteria. A) Time-lapse series of two cells making contact by gliding motility followed by TraA-TraA recognition (foci formation, arrow outline left) and then cargo transfer (GFP with lipoprotein signal sequence, white arrow) from the ‘donor’ to ‘recipient’ cell. The recipient cell expresses a TraA-mCherry fusion reporter that coalesces upon cell-cell contact. Note that the recipient cell reverses direction and once the cells disengage foci disappear (arrow outline right). Scale bar 1 μm. B) Schematic of OME where two adjacent cells recognizing each other by homotypic TraA interactions to form a TraAB OM fusion junction. Subsequently, transient membrane fusion allows the passive diffusion of proteins and lipids bidirectionally between cells. OM, outer membrane; IM, inner membrane.


Phenotypically, Tra-dependent OME leads to both beneficial and adversarial outcomes. For instance, under certain conditions damaged proteins or lipopolysaccharides in the cell envelop can be replaced and repaired by healthy partner cells, representing a helping cooperative behavior. In contrast, under different circumstances OME leads to policing or discrimination behaviors. These latter outcomes are driven by the exchange of a suite of polymorphic toxins that vary widely between myxobacteria isolates. Here, clonemate cells will express a suite of immunity proteins, which are not transferred, and thus confer self-resistance, while non-self-cells that happen to bear compatible TraA receptors will be poisoned. In summary, OME represents a new paradigm for how bacterial cells communicate, interact and transition from individuals into functional multicellular units. Our future studies are aimed at understanding the molecular details of cell-cell recognition, mechanism of outer membrane fusion and the social and evolutionary consequences of OME.

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Fig. 3. Self-recognition among a wide range of myxobacteria is governed by sequence variability in the TraA cell surface receptor. A) Model of the TraAB proteins in the cell envelop. B) Maximum likelihood tree consists of 59 myxobacterial TraA orthologs (variable domain). Solid lines indicate experimentally determined recognition groups (letters indicate groups), and dashed lines show predicted recognition groups. Shaded colors indicate key specificity residue at position 205. Scale bar indicates the number of substitutions per amino acid residue.


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Fig. 4. Tissue formation mediated by OME. A) Isogenic M. xanthus strains were mixed that harbor different fluorescent reporters (SSOM-GFP or SSOM-mCherry cellular cargo), which represent distinct adaptation states caused by growth in different environments. Top panels: Compatible TraA receptors allow exchange after a brief incubation. Bottom panels: In contrast, incompatible receptors prevent exchange. traA alleles shown at the left. Scale bar = 1 µm. B) Illustration of two kin populations that adapted to different microenvironments and are thus phenotypically divergent (top, labeled yellow and red). Following TraA-TraA recognition the groups merge into a homogeneous population or tissue through OME (orange). Black dots represent TraAB foci located at cell–cell contacts that are analogous to gap junctions in eukaryotic tissues.


Education

Postdoctoral Fellow, Stanford University, 1998

Ph.D., University of Utah, 1994

B.A., Sonoma State University, 1988


Professional Experience

Principal Scientist, Anadys Pharmaceuticals (acquired by Roche), 2006

Senior Scientist, Elitra Pharmaceuticals (acquired by Merck), 2002


Publications Last Five Years

Cao, P. and Wall, D. 2019. Direct visualization of a molecular handshake that governs kin recognition and tissue formation in myxobacteria. Nature Communications, 10, 3073.

Cao, P, Awal, R.P., Müller, R. and Wall, D. 2019. A highly polymorphic receptor governs many distinct self-recognition types within the Myxococcales order. mBio. 10:e02751-18.

Vassallo, C. and Wall, D. 2019. Self-identity barcodes encoded by six expansive polymorphic toxin families discriminate kin in myxobacteria. Submitted

Troselj, V., Treuner-Lange, A., Søgaard-Andersen, L. and Wall, D. 2018. Physiological heterogeneity triggers sibling conflict mediated by type VI secretion system in an aggregative multicellular bacterium. mBio 9:e01645-17.

Kitamura, S., Owensby, A. Wall, D. and Wolan, D. W. 2018. Novel lipoprotein signal peptidase inhibitors with antibiotic properties identified through design of a robust in vitro HT platform. Cell Chem. Biol. 25:1-8.

Patra, P., Vassallo, C.N., Wall, D. and Igoshin, O. 2017. Mechanism of kin-discriminatory demarcation line formation between growing colonies of swarming bacteria. Biophysical J. 113:2477-2486.

Troselj, V., Cao, P and Wall, D. 2017. Cell-cell recognition and social networking in bacteria. Environ. Microbiol. 10.1111/1462-2920.14005.

Vassallo, C.N., Cao, P., Conklin, A., Finkelstein, H., Hayes, C. and Wall, D. 2017. Infectious polymorphic toxins delivered by outer membrane exchange discriminate kin in myxobacteria. eLife 6:e29397.

Cao, P. and Wall, D. 2017. Self-identify reprogrammed by a single residue switch in a cell surface receptor of a social bacterium. PNAS. 114(14):3732-3737.

Wall, D. 2016. Kin recognition in bacteria. Annu. Rev. Microbiol. 70:143-1460.

Vassallo, C. and Wall, D. 2016. Tissue repair in myxobacteria: A cooperative strategy to heal cellular damage. BioEssays 38:306-315.

Dey, A., Vassallo, C. N., Conklin, A. C., Pathak, D. T., Troselj, V. and Wall, D. 2016. Sibling rivalry in Myxococcus xanthus is mediated by kin recognition and a polyploid prophage. J. Bacteriol. 198:994-1004.

Cao, P., Dey, A., Vassallo, C. and Wall, D. 2015. How myxobacteria cooperate. J. Mol. Biol. 427:3709-3721.

Vassallo, C., Pathak, D.T., Cao, P., Zuckerman, D.M., Hoiczyk, E and Wall, D. 2015. Cell rejuvenation and social behaviors promoted by LPS exchange in myxobacteria. PNAS. 112(22):E2939-46.

Dey, A. and Wall, D. 2014. A genetic screen in Myxococcus xanthus identifies mutants that uncouple outer membrane exchange from a downstream cellular response. J. Bacteriol. 196:4324-4332.

Wall, D. 2014. Molecular recognition in myxobacterial outer membrane exchange: Functional, social and evolutionary implications. Mol. Microbiol. 91:209-220.

Xiao, Y. and Wall, D. 2014. Genetic redundancy and proximity of lspA, the target of antibiotic TA, in the Myxococcus xanthus producer strain genome. J. Bacteriol. 196:1174-1183.

Wei, X., Vassallo, C.N., Pathak, D.T. and Wall, D. 2014. Myxobacteria produce outer membrane enclosed tubes in unstructured environments. J. Bacteriol. 196:1807-1814.

Wall, D. 2014. Social interactions mediated by outer membrane exchange. In Myxobacteria: Genomics, Cellular and Molecular Biology, edited by Yang, Z. & Higgs, P.I., Caister Academic Press, Norwich, U.K., pp 91-103.

Wall, D. 2014. DNA Cloning Strategies. In Reference Module in Biomedical Sciences, Elsevier Ltd, Oxford, U.K., doi:10.1016/B978-0-12-801238-3.02500-9.

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Department of Molecular Biology

University of Wyoming

Department #3944

1000 E. University Ave.

Laramie, WY 82071

Phone: (307) 766-3300

Fax: (307) 766-5098

Email: mbiology@uwyo.edu

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