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Open Forum on Cell Signaling

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Highlights from ASCB Symposium V (04 December 2007)

12 December 2007

John F. Foley

At the Tuesday morning symposium entitled "Geography of Signaling" the speakers were Deborah Hogan (Dartmouth Medical School), Howard Chang (Stanford University), and Elly Tanaka (Max Planck Institute Dresden).

Dr. Hogan discussed signaling in multicellular microbial communities, in particular about how microbes differentiate and develop within microbial biofilms. Biofilms are formed, for example, at the interface between liquid and air in a neglected bacterial culture, but can also occur when microbes form multicellular communities on surfaces, even on human tissues. Biofilms contain an extracellular matrix component, which is often derived from the microbes themselves, and microbes behave differently within the biofilm compared to their behavior in other environments.

Dr. Hogan explained that two organisms that are often found together in biofilms are the bacterium Pseudomonas aeruginosa and the yeast Candida albicans. P. aeruginosa use filamentous C. albicans as a substrate for biofilm formation, which kills the yeast in a process that is dependent on a form of P. aeruginosa phospholipase C. The unicellular (yeast) form of C. albicans is not bound to or killed by P. aeruginosa and mutant P. aeruginosa that cannot bind to filamentous C. albicans cannot kill it. When P. aeruginosa and filamentous C. albicans are grown together, any new C. albicans grow as single cells, even in the presence of cues for filamentous growth. This implied that C. albicans could sense a substance produced by the bacteria and respond by switching their morphology from a filamentous form, which is killed by P. aeruginosa, to a unicellular form, which can survive. A screen of P. aeruginosa identified 3-oxo-C12-homoserine lactone (3OC12HSL) as a factor that was sensed by C. albicans and prevented their filamentous growth.

In C. albicans, the pathway that determines filamentous growth is dependent on the activation of the small guanosine triphosphatase (GTPase) Ras, the subsequent stimulation of adenylyl cyclase, and the activation of cAMP-dependent protein kinase (PKA), which results in the activation of the transcription factor Efg1. 3OC12HSL inhibited this pathway and also induced stress response genes that were repressed by activated PKA. Examination of the effects of 3OH12HSL illustrated the connection in C. albicans between stress responses and morphology and showed that inhibition of the cAMP-dependent pathway leads to morphological changes and cell survival.

Dr. Chang discussed site-specific differences in the skin and the essential role of stromal cells from the underlying mesenchyme in directing the identities of the overlying epithelial cells. Dr. Chang used microarrays to show that stromal cells from 10 sites on the human adult body had distinct gene expression profiles, thus illustrating the genomic encoding of positional identity. These distinct gene expression patterns were determined by the expression of Hox genes, which encode transcription factors that are necessary for determining the embryonic body plan. Dr. Chang described how a combination of chromatin immunoprecipitation assays and microarray analyses revealed long non-coding RNAs and chromatin modifications contributed to site-specific Hox gene expression in the adult.

Dr. Tanaka spoke on the signaling mechanisms that regulate regeneration in vertebrates, with a focus on limb regeneration in the salamander, Axolotl. After amputation of a limb, a blastema forms under the wound tissue. Tissue-specific cells, from tissues such as skin, muscle, and cartilage, move to the blastema and it is from this zone that tissue regeneration occurs. Whether these tissue-specific cells retain their identity once they enter the blastema or revert to more primitive progenitor cells (in a process known as dedifferentiation) is the subject of much discussion in the field.

Through a series of elegant experiments involving amputation at various locations in the limb, the removal and relocation within the limb of cells of different tissue types, and the fluorescent labeling of tissue-specific cells, Dr. Tanaka argued that dedifferention of cells was not occurring in the blastema and that most, but not all, cell types can give rise only to their own specific tissue type in the regenerating limb. Dr. Tanaka also discussed the role of retinoic acid in the respecification of the blastema; for example, RA causes a blastema found near the hand to behave in a similar way to a blastema from the upper arm, which illustrated the relationship between tissue identity and position in the limb.

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