Non-apoptotic caspase-dependent regulation of enteroblast quiescence in Drosophila

Caspase malfunction in stem cells often instigates the appearance and progression of multiple types of cancer, including human colorectal cancer. However, the caspase-dependent regulation of intestinal stem cell properties remains poorly understood. Here, we demonstrate that Dronc, the Drosophila ortholog of caspase-9/2 in mammals, limits the proliferation of intestinal progenitor cells and prevents the premature differentiation of enteroblasts into enterocytes. Strikingly, these unexpected roles of Dronc are non-apoptotic and have been uncovered under experimental conditions without basal epithelial turnover. A novel set of genetic tools have also allowed us to correlate these Dronc functions with its specific accumulation and transient activation in enteroblasts. Finally, we establish that the Dronc-dependent regulation of enteroblast quiescence, largely relies on the fine-tuning of the Notch and Insulin-TOR signalling pathways. Together, this data provides novel insights into the caspase-dependent but non-apoptotic modulation of enteroblast differentiation in non-regenerative conditions. These findings could improve our understanding regarding the origin of caspase-related intestinal malignancies, and the efficacy of therapeutic interventions based on caspase-modulating molecules.