Understanding the role of Toll signalling in Drosophila midgut stem cell proliferation.

Thesis

The intestinal epithelium is a site of complex interaction between microbiome, epithelial cells, and the immune system through a multidirectional crosstalk achieved using signalling molecules and metabolites secreted by the microbiome and host cells. This cross talk maintains epithelial turnover and the gut microbial population while integrating nutrient absorption and host defence. In this context, innate immune pathways have been extensively studied to understand their role in the maintenance of microbial and epithelial homeostasis and to study the response against infections and stress. In mammals, Toll-Like Receptors (TLRs) have been widely researched for their role in maintaining the commensals and influencing the epithelial regeneration. However, the complexity of mammalian systems and inability to standardize the models makes it challenging to study interactions of TLRs with different pathways in the gut. The immune and developmental pathways involved in epithelial plasticity are evolutionarily conserved. Therefore, using Drosophila melanogaster as a model organism, we aim to understand the role of Toll signalling in regulating epithelial turnover during infection. To this end, we used a constitutively active form of Toll receptor to mimic Toll activation. Our results reveal that, the canonical Toll pathway was involved in the intestinal stem cell (ISC) proliferation. It also led to the enteroblasts getting blocked from differentiating and/or (mis)differentiating that caused accumulation of esg+ cells in the gut resulting in dysplasia. We found that the Jun N-terminal kinase (JNK) pathway was acting downstream of Toll in mediating Toll-induced dysplasia. Moreover, the developmental pathway Notch, had a potential antagonistic role upstream or in parallel to the Toll pathway. Taken together our results place Toll as the signalling element to integrate epithelial renewal and immune response.

Authors: Udayakumar, A

• DOI: 10.5287/ora-2aryymm6k
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: immunofluorescence; notch signalling; drosophila; JNK signalling; gut immunology; toll signalling; microbiome; intestinal stem cells; innate immunity; dysplasia
• Subjects: Drosophila melanogaster; Gut immunology; Immunology; Stem cells