Shaw, RL; (2012) Regulation of Drosophila intestinal regeneration by the Hippo pathway. Doctoral thesis , UCL (University College London).

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Abstract

Intestinal stem cells (ISCs) in the adult Drosophila midgut proliferate in order to self-renew and produce differentiating daughter cells that replace those lost as part of normal gut function. Intestinal stress induces the activation of Upd/Jak/Stat signalling, which promotes intestinal regeneration by inducing rapid SC proliferation and faster tissue turnover. I have investigated the role of the Hippo (Hpo) pathway in the Drosophila midgut. The Hpo pathway regulates tissue size via the control of both apoptosis and proliferation during Drosophila development. In the midgut, Hpo pathway inactivation in either the SCs or their differentiated daughter cells, the enterocytes (ECs), induces a phenotype similar to that observed under stress situations, including increased proliferation and expression of Upd cytokines. Hpo pathway targets are induced by stresses such as bacterial infection, suggesting that the pathway functions as a sensor of cellular stress in the ECs. In addition, Yki, the pro-growth transcription factor target of the pathway, is required in ISCs to drive the proliferative response to stress. Yki inactivation has no obvious effect on baseline homeostasis, while survival upon infection is affected by loss of Yki in either the ISCs or ECs. My findings suggest that the Hpo pathway is a mediator of the regenerative response in the midgut. In the final part of the project, I have addressed possible mechanisms of Yki activation, with a view to gaining further insight into Yki function in the ECs. The data suggest a possible link between the generation of reactive oxygen species, JNK signalling and Yki activation. Several explanations could account for the requirement of Yki expression in the ECs. Yki expression itself might induce stress in the ECs, leading to upd expression and the regenerative response. Alternatively, the Hpo pathway might function as a stress sensor, triggering Upd release in response to noxious stimuli.

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