Drosophila AHR limits tumor growth and stem cell proliferation in the intestine

<ns3:p> Background The aryl hydrocarbon receptor (AHR) plays important roles in intestinal homeostasis, limiting tumour growth and promoting differentiation in the intestinal epithelium. Spineless, the <ns3:italic>Drosophila</ns3:italic> homolog of AHR, has only been studied in the context of development but not in the adult intestine. Methods The role of Spineless in the <ns3:italic>Drosophila</ns3:italic> midgut was studied by overexpression or inactivation of Spineless in infection and tumour models and RNA sequencing of sorted midgut progenitor cells. Results We show that <ns3:italic>spineless</ns3:italic> is upregulated in the adult intestinal epithelium after infection with <ns3:italic>Pseudomonas entomophila</ns3:italic> ( <ns3:italic>P</ns3:italic> . <ns3:italic>e</ns3:italic> .). Spineless inactivation increased stem cell proliferation following infection-induced injury. Spineless overexpression limited intestinal stem cell proliferation and reduced survival after infection. In two tumour models, using either <ns3:italic>Notch</ns3:italic> RNAi or constitutively active Yorkie, Spineless suppressed tumour growth and doubled the lifespan of tumour-bearing flies. At the transcriptional level it reversed the gene expression changes induced in Yorkie tumours, counteracting cell proliferation and altered metabolism. Conclusions These findings demonstrate a new role for Spineless in the adult <ns3:italic>Drosophila</ns3:italic> midgut and highlight the evolutionarily conserved functions of AHR/Spineless in the control of proliferation and differentiation of the intestinal epithelium. </ns3:p>