Revealing how cells read the environment to regulate adult gut renewal (360G-Wellcome-206208_Z_17_Z)

The intestinal epithelium constantly regenerates from stem cells which adjust their behaviour to the changing physiological conditions the gut is exposed to. For example, stem cell proliferation rates can transiently increase to speed up regeneration after tissue loss, or in response to the diet, before reverting to steady-state levels once correct tissue size is reached. This plasticity is essential for intestinal function, as lack of regeneration causes tissue atrophy whereas unrestricted stem cell proliferation causes cancer. I propose to use the genetically tractable Drosophila gut to identify the secreted and physical factors regulating gut plasticity. Thanks to targeted genetic screens done in contexts that trigger reversible changes in gut size and functional analyses, I will identify novel extracellular signalling molecules regulating cell proliferation. I will also examine the relationships between physical remodelling of the gut and stem cell proliferation by characterising the transcriptional output of integrin signaling and establishing how physical remodelling of the visceral mesoderm (a source of growth factors in the gut) contributes to regenerate the intestinal epithelium. As the regulation of intestinal proliferation is largely conserved between Drosophila and mammals this work has the potential to uncover important new principles relevant to intestinal maintenance and degenerative diseases.