Brindle, Nicola Rae; (2019) Investigating a role for Calcineurin in the regulation of the Hippo pathway in Drosophila Melanogaster. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

How do organisms “know” when to stop growing? Why do our internal organs grow to a characteristic size and shape? These are fundamental biological questions to which we still do not have complete answers. At the molecular level, multiple pathways controlling developmental growth have been identified. However, how these are regulated and coordinated at a systemic level to achieve proportional growth of an organism is an as yet unanswered question. The Hippo signalling pathway is a major developmental growth control pathway which sits downstream of multiple and diverse upstream signalling inputs. It regulates the intrinsic control of organ size, but more recently roles for Hippo signalling have been identified in systemic control of growth. As such, the Hippo pathway has been proposed to be a nodal point for regulation of organismal growth. In addition to intrinsic signals, organisms must also respond to their environment, and therefore extrinsic cues are also important regulators of developmental growth. Nutrition is a key extrinsic determinant of size control. Prolonged starvation during development results in smaller adults, whereas excess nutrition can lead to metabolic pathologies such as diabetes and obesity both of which are risk factors for other diseases e.g. cancer, a disease of uncontrolled growth. Thus, either too much or too little nutritional input can adversely affect growth control. The aim of this thesis is to explore the link between Hippo signalling and the nutritionally regulated calcium and calmodulin dependent phosphatase Calcineurin (Cn). Cn acts antagonistically to Salt Inducible Kinases (Siks) in the nutrient-dependent regulation of transcriptional coactivators involved in the regulation of fasting responses. Siks were previously identified as negative regulators of Hippo signalling. Here it is shown that in vitro Cn antagonises Sik-mediated regulation of Hippo signalling. Additionally, the results suggest a novel mechanism by which Cn may directly regulate Sik activity through dephosphorylation of the T-loop threonine. In vivo, reducing Cn function synergises with activated Sik2 to promote pro-proliferative Yki activity in wing imaginal discs and ovarian follicle cells. Furthermore, Cn affects systemic growth when expressed in the prothoracic gland, phenocopying the increased pupal volume observed upon loss of Warts function in this tissue. The results from this study suggest a role for Cn in regulation of Hippo signalling, however the physiological significance of Hippo regulation by Cn and Sik in response to the nutritional environment remains to be further explored.

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