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Review
. 2017 Jan;33(1):3-15.
doi: 10.1016/j.tig.2016.10.006. Epub 2016 Dec 2.

Highly Signal-Responsive Gene Regulatory Network Governing Myxococcus Development

Lee Kroos  1
Affiliations
Review

Highly Signal-Responsive Gene Regulatory Network Governing Myxococcus Development

Lee Kroos. Trends Genet. 2017 Jan.

Abstract

The bacterium Myxococcus xanthus undergoes multicellular development when starved. Thousands of cells build mounds in which some differentiate into spores. This remarkable feat and the genetic tractability of Myxococcus provide a unique opportunity to understand the evolution of gene regulatory networks (GRNs). Recent work has revealed a GRN involving interconnected cascades of signal-responsive transcriptional activators. Initially, starvation-induced intracellular signals direct changes in gene expression. Subsequently, self-generated extracellular signals provide morphological cues that regulate certain transcriptional activators. However, signals for many of the activators remain to be discovered. A key insight is that activators often work combinatorially, allowing signal integration. The Myxococcus GRN differs strikingly from those governing sporulation of Bacillus and Streptomyces, suggesting that Myxococcus evolved a highly signal-responsive GRN to enable complex multicellular development.

Keywords: Myxococcus xanthus; bacterial development; gene regulatory network; signal transduction; sporulation.

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Figures

Figure I
Figure I
Figure 1
Figure 1. Myxococcus Fruiting Body Formation
(A) Cartoon representation. When growing cells (yellow) become starved, they undergo aggregation and form a mound. Many cells lyse (dashed white cell outlines) during aggregation. Some of the rods differentiate into ovoid spores in the mound, resulting in a fruiting body. Other cells remain outside fruiting bodies as peripheral rods (orange). Depending on the strain and conditions, aggregation takes 1–2 days and spores form over the following 2–4 days. The process involves a much larger number of cells than depicted. (B) Scanning electron micrographs. The micrographs are aligned with the cartoon representation to show the sequence of morphological changes (left to right) from early aggregates [individual cells are barely visible as long (~5 μm), slender (~0.5 μm) rods] to mounds to fruiting bodies (~100 μm tall) that if cracked open reveal spores (~1 μm). Micrographs are from [87] with permission.
Figure 2
Figure 2. Overview of the Gene Regulatory Network Governing Myxococcus Fruiting Body Formation
Starvation triggers the Mrp (orange) and EBP cascade (blue) modules, and causes the second messengers c-di-GMP and (p)ppGpp to accumulate in cells. c-di-GMP binds to Nla24 (probably phosphorylated Nla24), the key transcription factor of the Nla24 module (red), activating genes for synthesis of exopolysaccharide (EPS) needed for fruiting body formation. (p)ppGpp causes extracellular A- and C-signals to be produced. A-signal provides quorum sensing for the decision to begin aggregation. C-signal is a short-range (possibly contact-dependent) signal that activates FruA (depicted as FruA*) (Box 1). FruA* and MrpC are transcription factor outputs of the FruA module (green) and the Mrp module, respectively, which separately and together regulate genes important for fruiting body formation. MrpC activates transcription of fruA. The EBP cascade stimulates the Mrp module, production of three signals, FruA* formation, and transcription of genes important for fruiting body formation. Feedback loops are omitted for simplicity. Adapted from [22].
Figure 3 Key Figure
Figure 3 Key Figure. The Gene Regulatory Network before and during Myxococcus Aggregation
Early events are shown in more detail than in Figure 2 and the same color scheme is used for the four modules (EBP cascade, blue; Nla24, red; Mrp, orange; FruA, green). Feedback loops, including autoregulatory ones, are also shown in this figure. Transcription factors are boxed. Arrows and lines with a barred end indicate positive and negative regulation, respectively. The EBP cascade is shown connected to the MrpC/FruA* cascade since Nla28~P appears to activate transcription of mrpAB (arrow from Nla28~P to MrpB~P) and MrpB~P appears to activate transcription of mrpC. (p)ppGpp is necessary for production of C-signal (Box 1), but this is omitted for clarity. FruA is activated posttranscriptionally by C-signal and by MXAN4899~P acting alone and/or in combination with HsfA~P (?), but the mechanisms of activation are unknown (Box 1). FruA* stimulates aggregation, enhancing short-range C-signaling (Box 1), which is depicted as positive feedback of FruA* directly on C-signal, for simplicity. See the text for details and references.
Figure 4
Figure 4. Cooperative Binding of MrpC and FruA at Promoter Regions May Explain Differential Dependence on C-signal
The two transcription factors bind in different arrangements immediately upstream of the promoter −35 and −10 sequences, and activate transcription (+). In the fmgD promoter region, a second MrpC binding site overlaps the promoter −35 sequence and the FruA binding site, which is proposed to cause stronger dependence on C-signal activation of FruA (column at right) in order to overcome the negative effect of MrpC (−). Larger regions around the dev and fmgE promoters show the approximate position (relative to the transcriptional start site) and the effect on promoter activity (positive, +; negative, −) of distal cooperative binding sites. The negative regulatory site at −100 may compete with the fmgE promoter proximal site for cooperative binding of MrpC and FruA*, explaining the strong dependence on C-signal.
Figure 5
Figure 5. The Gene Regulatory Network Governing Myxococcus Sporulation
The same color scheme is used as in Figures 2 and 3 for the Mrp (orange) and FruA (green) modules, but less detail about early events is shown. The MrpC/FruA* transcription factor cascade is emphasized. C-signal and MXAN4899~P (possibly with HsfA~P, Figure 3) activate FruA by unknown mechanisms (Box 1). Cells brought into proximity during aggregation are proposed to engage in efficient C-signaling that serves as a morphological cue and results in a rising level of FruA*, which separately and in combination with MrpC activates genes whose products promote further aggregation and eventually sporulation. Overexpression of DevI in devTRS mutants inhibits sporulation, perhaps by inhibiting Exo expression [69, 88] (not shown). See the text for details and references.
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