Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677715
Title: The genetic basis of cell fate bias and biased responses in Dictyostelium discoideum
Author: Chattwood, Alex
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2010
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Abstract:
The generation of pattern is one of the most important features of multicellular development. One idea gaining recognition is pattern formation in the absence of positional information. In this, different cell types differentiate within an identical signalling environment before sorting out to form discrete tissues. Positional models cannot explain how symmetry is broken under these conditions because the amount of signal received by each individual cell is the same. However, fate choice is possible if the cells interpret the signal they receive differently. Dictyostelium discoideum provides an excellent model with which to study this patterning mechanism because different prestalk cell types arise scattered in response to the diffusible signalling molecule DIF-1 (DIF). Those cells that respond to DIF are intrinsically more DIF sensitive due to biases caused by growth history (e.g. nutrition, cell cycle, etc). One clue as to how biases operate at a molecular level has come from studies of the rblA- mutant. From these studies, RblA has been proposed to be a central mediator of cell fate bias. Surprisingly, however, we have found that careful examination of bias effects (using cell type specific markers) caused by nutritional status and RblA mutation actually showed considerable differences. Most notably, although both affect DIF dependent pstB cell differentiation only mutation of RblA affects DIF dependent pstO cell differentiation. These studies therefore suggest that biased decisions exhibit greater molecular complexity and cell type specificity than might have been expected. To test this idea, we devised a genetic selection to identify novel regulators of cell fate bias in which the interpretation of nutritional bias was affected. One such mutant contained a disruption of GefE, an activator of RasD. Cell type marker expression studies reveal GefE regulation coordinates the same biases as nutritional status. We also show that GefE and RblA antagonistically regulate DIF dependent pstB cell differentiation in normal development but have distinct roles in other cell types. DIF response assays on rblA- and gefE- mutant strains suggest they antagonistically control the threshold at which a DIF-1 sensitivity switch can be turned on/off. We therefore propose a mechanism whereby DIF signalling drives and maintains differentiation in several cell types based upon the activity of multiple bias switches. In this way, diverse cellular responses can be integrated via a common signal.
Supervisor: Garrod, David ; Thompson, Christopher Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.677715  DOI: Not available
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