Notch and EGFR regulate apoptosis in progenitor cells to ensure gut homeostasis in Drosophila

Abstract

The regenerative activity of adult stem cells carries a risk of cancer, particularly in highly renewable tissues. Members of the family of inhibitor of apoptosis proteins (IAPs) inhibit caspases and cell death, and are often deregulated in adult cancers; however, their roles in normal adult tissue homeostasis are unclear. Here, we show that regulation of the number of enterocyte‐committed progenitor (enteroblast) cells in the adult Drosophila involves a caspase‐mediated physiological apoptosis, which adaptively eliminates excess enteroblast cells produced by intestinal stem cells (ISCs) and, when blocked, can also lead to tumorigenesis. Importantly, we found that Diap1 is expressed by enteroblast cells and that loss and gain of Diap1 led to changes in enteroblast numbers. We also found that antagonistic interplay between Notch and EGFR signalling governs enteroblast life/death decisions via the Klumpfuss/WT1 and Lozenge/RUNX transcription regulators, which also regulate enteroblast differentiation and cell fate plasticity. These data provide new insights into how caspases drive adult tissue renewal and protect against the formation of tumours.

Ecdysone steroid hormone remote controls intestinal stem cell fate decisions via the PPARγ-homolog Eip75B in Drosophila

“…background transgene expression or position effects most probably caused by the total number of six transgenes including esg ReDDM . PMG of >Kr-h1 combinations also showed some progenitor lethality indicated by membrane-blebbing and irregularities (arrowheads, E-G) as described in (Reiff et al 2019). (J) Quantification of progenitor numbers (I) and traced progeny encompassing EC and EE (J) in R5 PMG (n=12,5,9,8,7,13,8,8,13).…”

“…Korzelius et al 2019, Reiff et al 2019. We used klu ReDDM to explore the function of EcR and Eip75B in EB lineage identity (Figure 3 -figure supplement 2A).…”

Ecdysone steroid hormone remote controls intestinal stem cell fate decisions via thePPARγ-homologEip75BinDrosophila

“…Figure 7-figure supplement 1A-C) and forced expression of >E75A/-C to instant EC formation (Figure 7-figure supplement 1D-E). Interestingly, in the presence of N, its activity is increased upon RH5849 feeding(Figure 7 -figure supplement 1F), which suggests an interplay between Notch and EcR-signaling that might converge on Eip75B (this study) and klu(Korzelius et al 2019, Reiff et al 2019.…”

“…background transgene expression or position effects most probably caused by the total number of six transgenes including esg ReDDM . PMG of >Kr-h1 combinations also showed some progenitor lethality indicated by membrane-blebbing and irregularities (arrowheads, E-G) as described in (Reiff et al 2019). (J)…”

“…Nine out of ten ISC mitosis give rise to EB specified by N-activation in EB daughters (Micchelli & Perrimon 2006, Ohlstein & Spradling 2006, Ohlstein & Spradling 2007. Post-mitotic EB retain a certain degree of plasticity by: (1) delaying their terminal differentiation through mesenchymal-to-epithelial transition (MET) (Antonello et al 2015a), (2) changing their fate to EE upon loss of the transcription factor klu (klumpfuss) and (3) undergoing apoptosis as an additional homeostatic mechanism (Korzelius et al 2019, Reiff et al 2019.…”