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c-di-GMP signalling and the regulation of developmental transitions in streptomycetes

Key Points

  • The erection of reproductive aerial hyphae and sporulation septation are the two most striking developmental transitions in the life cycle of filamentous streptomycete bacteria. Recent advances in our understanding of how these developmental transitions are controlled have revealed a coherent regulatory network that now allows us to draw direct connections from specific regulators to the cell biological processes associated with major morphogenetic events.

  • BldD has emerged as a master regulator that oversees the entire regulatory cascade through the repression of a global regulon of 170 sporulation genes during vegetative growth. This regulon includes almost all of the genes of the core transcriptional regulatory cascade, as well as genes encoding critical components of the cell division and chromosome segregation machineries required for sporulation.

  • BldD-mediated repression requires the second messenger cyclic di-GMP (c-di-GMP), which binds to BldD as a co-repressor to control the decision to initiate the developmental programme. A high level of c-di-GMP blocks the formation of aerial hyphae and spores until a drop in the level of c-di-GMP relieves BldD-mediated repression of the regulatory cascade.

  • To allow aerial hyphae to emerge into the air, streptomycetes cover these structures in an extremely hydrophobic sheath, composed of two families of proteins called the chaplins and rodlins. The developmental regulator sigma factor σBldN is responsible for activating the expression of all of the chaplin and rodlin genes; σBldN is in turn regulated by the transmembrane anti-sigma factor RsbN.

  • Chromosome replication is upregulated in each aerial hypha before sporulation septation, leading to a single, long 'sporogenic cell' containing 50–100 copies of the chromosome. The developmental regulator AdpA, long known to function as a conventional transcription factor for a large regulon of sporulation genes, also controls developmental chromosome replication by binding to two sites in the 5′ region of the origin of replication (oriC).

  • Transcriptional regulation of differentiation is common throughout all living systems, but an extremely unusual feature of sporulation in streptomycetes is that these bacteria have appropriated the only tRNA that can translate TTA codons (the BldA tRNA) for a very specific role as a developmental regulator. This tRNA forms part of a unique positive feedback loop in which AdpA activates transcription of bldA and the BldA tRNA is in turn required for expression of adpA, which has a TTA codon.

  • The cessation of aerial growth is tightly coordinated with the initiation of sporulation septation, and both these processes are controlled by the transcription factors WhiA and WhiB. During this transition, WhiA directly represses the transcription of filP, encoding a protein that forms part of the polarisome that directs cell wall synthesis at the growing hyphal tip, and directly activates many key components of the sporulation septation machinery, including ftsK, ftsW and ftsZ.

  • Heterodimer formation between two orphan, atypical response regulators, BldM and WhiI, activates genes required for spore maturation. Although BldM functions as a homodimer during early development, WhiI functions solely as an auxiliary protein to modulate BldM binding specificity and there is no set of genes regulated by a WhiI homodimer.


The complex life cycle of streptomycetes involves two distinct filamentous cell forms: the growing (or vegetative) hyphae and the reproductive (or aerial) hyphae, which differentiate into long chains of spores. Until recently, little was known about the signalling pathways that regulate the developmental transitions leading to sporulation. In this Review, we discuss important new insights into these pathways that have led to the emergence of a coherent regulatory network, focusing on the erection of aerial hyphae and the synchronous cell division event that produces dozens of unigenomic spores. In particular, we highlight the role of cyclic di-GMP (c-di-GMP) in controlling the initiation of development, and the role of the master regulator BldD in mediating c-di-GMP signalling.

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Figure 1: The life cycle of streptomycetes.
Figure 2: BldD is a master regulator of development in streptomycetes.
Figure 3: c-di-GMP signals through the repressor BldD to control development.
Figure 4: Regulation of developmental processes during the erection of aerial hyphae.


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Correspondence to Mark J. Buttner.

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The collective term for a mass of hyphae, such as the vegetative mycelium within the medium or the reproductive aerial mycelium on the colony surface.

Surfactant peptide

A peptide that functions to reduce the surface tension of water.


One of a class of small, high-affinity iron-chelating compounds that are secreted by bacteria and other microorganisms.


Sets of genes, each of which is under the direct control of a given transcription factor.

Second messenger

One of a class of small, intracellular molecules that relay a signal perceived from the outside of the cell to an effector protein (or riboswitch) within the cytoplasm.


A description for single cells that can float or swim in water.


(PDEs). Enzymes that break phosphodiester bonds.


A member of the branch of Gram-positive bacteria to which the genus Streptomyces belongs, which is notable for the high GC content of genomes.

DNA translocase

A protein that pumps, or translocates, DNA using the energy of ATP hydrolysis.


An enclosure in which spores are formed.


(chromatin immunoprecipitation followed by sequencing). An in vivo method to identify the genomic binding sites of a given transcription factor.

Sigma factors

Proteins that direct the binding of RNA polymerase to promoters, enabling the initiation of transcription.

Anti-sigma factor

An antagonistic protein that binds to its cognate sigma factor, thereby preventing the sigma factor from interacting with RNA polymerase.

Initiator protein

A protein that recognizes the origin of replication and promotes the unwinding of double-stranded DNA before replication.

Lipid II flippase

A protein responsible for translocating lipid-attached cell wall precursors to the outside of the cytoplasmic membrane.

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Bush, M., Tschowri, N., Schlimpert, S. et al. c-di-GMP signalling and the regulation of developmental transitions in streptomycetes. Nat Rev Microbiol 13, 749–760 (2015).

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