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

Abstract

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.