Non-apoptotic enteroblast-specific role of the initiator caspase Dronc for development and homeostasis of the Drosophila intestine

Abstract

The initiator caspase Dronc is the only CARD-domain containing caspase in Drosophila and is essential for apoptosis. Here, we report that homozygous dronc mutant adult animals are short-lived due to the presence of a poorly developed, defective and leaky intestine. Interestingly, this mutant phenotype can be significantly rescued by enteroblast-specific expression of dronc+ in dronc mutant animals, suggesting that proper Dronc function specifically in enteroblasts, one of four cell types in the intestine, is critical for normal development of the intestine. Furthermore, enteroblast-specific knockdown of dronc in adult intestines triggers hyperplasia and differentiation defects. These enteroblast-specific functions of Dronc do not require the apoptotic pathway and thus occur in a non-apoptotic manner. In summary, we demonstrate that an apoptotic initiator caspase has a very critical non-apoptotic function for normal development and for the control of the cell lineage in the adult midgut and therefore for proper physiology and homeostasis.

A feedback loop that drives cell death and proliferation and its defect in intestinal stem cells

“…The epigenetic regulation of rpr is similar to its regulation in the salivary gland ( Zhang et al, 2014 ), and distinct from apoptosis resistance in cell cycle–arrested cells ( Ruiz-Losada et al, 2022 ). The role that caspases play in ISCs is distinct from their apoptotic or non-apoptotic roles in enteroblasts ( Reiff et al, 2019 ; Arthurton et al, 2020 ; Lindblad et al, 2021 ). Because the ancestral status such as the preservation of genes that predate animal origin is a key feature of tissue stem cells ( Alie et al, 2015 ), we speculate that ISCs may accomplish their relative immortality by keeping the ancestral role of caspases.…”

The Duality of Caspases in Cancer, as Told through the Fly

“…Recent research paints a complex picture of caspase activity, outside their established apoptotic and inflammatory roles, with caspase activity being involved in a wide range of other fundamental cellular processes, including development, aging, proliferation, differentiation, and neuronal plasticity [50][51][52][53][54][55][56]. The collection of non-apoptotic caspase functions have been termed caspase-dependent non-lethal cellular processes (CDPs) [44].…”

“…The underlying mechanisms of these caspase functions await to be further explored in order to understand their physiological and pathological relevance. Recent studies using the adult Drosophila midgut, functionally equivalent to the mammalian small intestine, have led to some interesting insights [50,56].…”

“…A recently developed genetic reporter of the initiator caspase Dronc revealed that it activates in both ISC and EB cells in the midgut [103]. Subsequent studies further showed that conditional knockout of Dronc in both ISCs and EBs or RNAi knockdown of Dronc specifically in EBs causes increased cell proliferation leading to hyperplasia as well as promotes differentiation of EBs into ECs and EEs [50,56]. Moreover, the catalytic function of Dronc, but not the apoptotic cascade, is required in these processes.…”

Regenerative clustering of Enteroblasts in theDrosophilamidgut revealed by a morphometric analysis

“…In one study, manipulating Zfh2 levels in both ISCs and EBs led to differential effects on cell area and circularity (Rojas Villa et al, 2019). In another study, knock down of dronc affected EB shape and size, though only size was quantified (Lindblad et al, 2021). These studies are evidence that gene effects on cell status can be reflected through their morphological changes.…”