Cytokine/Jak/Stat Signaling Mediates Regeneration and Homeostasis in the Drosophila Midgut

Abstract

SUMMARY Cells in intestinal epithelia turn over rapidly due to damage from digestion and toxins produced by the enteric microbiota. Gut homeostasis is maintained by intestinal stem cells (ISCs) that divide to replenish the intestinal epithelium, but little is known about how ISC division and differentiation are coordinated with epithelial cell loss. We show here that when enterocytes (ECs) in the Drosophila midgut are subjected to apoptosis, enteric infection, or JNK-mediated stress signaling, they produce cytokines (Upd, Upd2, Upd3) that activate Jak/Stat signaling in ISCs, promoting their rapid division. Upd/Jak/Stat activity also promotes progenitor cell differentiation, in part by stimulating Delta/Notch signaling, and is required for differentiation in both normal and regenerating midguts. Hence, cytokine-mediated feedback enables stem cells to replace spent progeny as they are lost, thereby establishing gut homeostasis.

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

“…UAS‐Flybow 1.1 [Bloomington Drosophila Stock Centre (BDSC): 35537, (Hadjieconomou et al , 2011)], UAS‐StGFP ( UAS‐Stinger , (Barolo et al , 2000), gift from M. Landgraf), UAS‐Dcr2 ( UAS‐Dicer2 , (Dietzl et al , 2007), gift from I. Salecker), UAS‐Ret [ UAS‐Ret‐3xFLAG‐6xHis (Kallijarvi et al , 2012)]; UAS‐upd1 (Jiang et al , 2009; gift from J. Cordero); UAS‐sspitz [Schweitzer et al , 1995; gift from J. Treisman); UAS‐wg ( UAS‐wg::HA , BDSC:5918); UAS‐sgg DN ( UAS‐sgg.A81T , BDSC: 5360, (Bourouis, 2002)]; UAS‐dsh DN ( UAS‐dshΔB21‐2 , (Axelrod et al , 1998), gift from J. Axelrod); UAS‐pan DN (van de Wetering et al , 1997; gift from F.J. Díaz‐Benjumea); UAS‐Src42A CA (BDSC: 6410); UAS‐Dcr2 (VDRC Stock Centre: 60007); UAS‐Ret‐RNAi (VDRC: GD 843); UAS‐dsh‐RNAi (VDRC: KK 101525); UAS‐Src42A‐RNAi (VDRC:KK 100708); UAS‐Src64B‐RNAi (VDRC: GD 35252), UAS‐Fak (Palmer et al , 1999). …”

Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies

“…This was demonstrated in Bmi1 cells using gamma-irradiation [28,29,33] and in Drosophila ISCs with the DNA damaging agent bleomycin [61]. These studies show that Bmi1 cells and Drosophila ISCs are not only resistant, but also exhibit compensatory growth to replace injured cells in the epithelium, such as Lgr5 cells in mammals and ECs in flies [61,62]. Thus, the Drosophila ISCs resemble behaviors of both the Lgr5 'everyday cycling stem cells' as well as Bmi1 'reserve stem cells' of the mammalian intestine.…”

Le dialogue microbiote-cellules souches

“…Plusieurs études réalisées chez la drosophile ont montré que le microbiote intestinal jouait un rôle important dans la régulation de la prolifération des CSI [25]. Cette régulation semble en grande partie relayée par les entérocytes qui, en réponse au stimulus bactérien, activent la prolifération des CSI via la signalisation JAK/ STAT (Janus kinases/signal transducers and activators of transcription) [28,29], ou la signalisation Redox (oxydo-réduction), à la suite de l'activation de NOX1 (NADPH oxydase 1), un complexe enzymatique membranaire exprimé par les cellules épithéliales et responsable de la libération de ROS (reactive oxygen species) [30]. Le pic oxydatif résultant de l'activation de NOX1 a éga-lement été impliqué dans la cytoprotection des CSI.…”