The regulation of life cycle differentiation in African trypanosomes.

Trypanosomes prepare for tsetse transmission by generating stumpy-forms. These are non-proliferative forms that arise via a quorum-sensing mechanism as parasites accumulate in the mammalian bloodstream. Stumpy forms are pre-adapted for differentiation to procyclic-forms in the tsetse-midgut, a process that can be readily reproduced and manipulated in vitro. In the last 5 years we have discovered the first central-regulator of stumpy-differentiation (Szoor et al, J Cell Biol, 2006), have identif ied the surface molecule that transmits the primary differentiation-signal (Dean et al, Nature, in revision) and have established a novel RNA-binding protein family as key regulators of differentiation events in the tsetse-fly (Paterou et al, J Biol Chem, 2006). In this proposal we will exploit these new discoveries and reagents to investigate how the trypanosome optimises its ability to be transmitted to tsetse flies and the molecular mechanisms of gene expression that underpin its development to procyclic-forms. Specifically we will: 1. Discover how stumpy-forms prepare for differentiation by investigating molecules specifically expressed in that life-cycle stage, their regulation and function. 2. Use already-identified markers for stumpy-forms as reporters to investigate the T.brucei quorum-sensing pathway 3. Dissect the machinery of gene regulation during differentiation to understand developmentally regulated changes in protein expression.