Identification and characterisation of a novel enterocyte sensor

Abstract

The gut is becoming increasingly well recognised as an important nutrient-sensing endocrine organ, which can regulate its own functions as well as those of other organs. Previous work has established that a subpopulation of cells in the intestinal epithelium - the enteroendocrine cells - can release hormones in response to nutritional stimuli. However, there is some evidence that a second epithelial population - the absorptive enterocytes - is also capable of responding to dietary content. The aim of this project was to identify a new mechanism by which this might occur. Using the model organism Drosophila melanogaster, I conducted an enterocyte-specific RNAi screen of over 100 candidate transporter and receptor genes. This screen identified CG11340 (Hodor), for which knockdown consistently caused an increase in the time taken for larvae to develop into pupae, particularly in poor-nutritional conditions. Hodor encodes a cys-loop ligand-gated ion channel, which is a class of protein usually associated with post-synaptic membranes. I have confirmed that Hodor protein is found in the gut and have further analysed its cell type-specific expression and subcellular distribution. I have also identified a novel ligand for Hodor and characterised its activity in vitro. Loss of this protein in enterocytes of larvae reared on a low-nutrient diet dramatically reduced food intake, and had striking consequences both for the gut and for the organism as a whole. These results underscore the importance of enterocytes in mediating adaptations to nutrient scarcity, and identify Hodor as a gene that plays a key role in this process.