Non‐apoptotic caspase activation preserves Drosophila intestinal progenitor cells in quiescence

Abstract

Caspase malfunction in stem cells often precedes 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 number of intestinal progenitor cells and their entry into the enterocyte differentiation programme. Strikingly, these unexpected roles for Dronc are non‐apoptotic and have been uncovered under experimental conditions without epithelial replenishment. Supporting the non‐apoptotic nature of these functions, we show that they require the enzymatic activity of Dronc, but are largely independent of the apoptotic pathway. Alternatively, our genetic and functional data suggest that they are linked to the caspase‐mediated regulation of Notch signalling. Our findings provide novel insights into the non‐apoptotic, caspase‐dependent modulation of stem cell properties that could improve our understanding of the origin of intestinal malignancies. image Non‐apoptotic activation of the initiator caspase Dronc contributes to preserving intestinal progenitor cells in a quiescent, non‐proliferative and undifferentiated state under experimental conditions without epithelial replenishment demand. The prevalent accumulation and transient activation of Dronc maintains intestinal progenitor cells in quiescence under non‐regenerative conditions. Dronc promotes quiescence independent of the apoptosis program and in part through the negative and Dronc‐dependent regulation of Notch‐signalling. Caspase activation can prevent gut hyperplasia, and act as a tumour‐suppressor factor through non‐apoptotic mechanisms related to the regulation of stem cells properties.