Regulation of development in Myxococcus xanthus by the second messenger c-di-GMP

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Cells of Myxococcus xanthus initiates developmental programme in response to nutrient starvation that culminates in the formation of spore-filled fruiting bodies. Completion of this developmental programme crucially depends on the close coordination of temporally regulated changes in gene expression, motility and its regulation, intercellular signaling, as well as signaling by nucleotide-based second messengers. These second messengers include (p)ppGpp synthesized by RelA and, as we have recently shown, c-di-GMP. c-di-GMP accumulates at elevated levels during starvation in comparison to vegetatively growing cells and this increase is essential for completion of development whereas excess c-di-GMP does not interfere with development. The enzymatically active diguanylate cyclase DmxB is essential for development and responsible for this increase in the c-di-GMP level. Also, we have demonstrated that DmxB is only synthesized during development and functions to stimulate exopolysaccharide accumulation by inducing transcription of genes involved in exopolysaccharide synthesis. Our data support the hypothesis that DmxB is regulated at multiple levels including transcription, allosterically and by phosphorylation of its N-terminal receiver domain. Because DmxB can partially be functionally replaced by a heterologous diguanylate cyclase these data suggest that a minimum threshold level of c-di-GMP is essential for successful completion of this multicellular developmental program. We have also identified the enzymatically active phosphodiesterase PmxA as essential for development, however, lack of PmxA does not cause a change in the global cellular level of c-di-GMP. The ultimate goals of this project are to understand how c-di-GMP accumulation is regulated during development in M. xanthus and to identify the effector proteins that bind c-di-GMP and implement the effects of changing c-di-GMP levels. To this end, we will focus on three lines of integrated research in the first 3-year funding period of this Priority Programme. Firstly, we aim to identify the sensory input(s) that regulates the development-specific diguanylate cyclase DmxB. Secondly, we aim to identify c-di-GMP binding effector proteins that are active during development. Thirdly, we aim to determine the mechanism of the development-specific phosphodiesterase PmxA.