Steroid hormone-induced wingless ligands tune female intestinal size in Drosophila.

Abstract

Female reproduction comes at great expense to energy metabolism compensated by extensive organ adaptations including intestinal size. Upon mating, endocrine signals orchestrate a 30% net increase of absorptive epithelium. Mating increases production of the steroid hormone Ecdysone released by the Drosophila ovaries that stimulates intestinal stem cell (ISC) divisions. Here, we uncover the transcription factor crooked legs (crol) as an intraepithelial coordinator of Ecdysone-induced ISC mitosis. For the precise investigation of non-autonomous factors on ISC behaviour, we establish Rapport, a spatiotemporally-controlled dual expression and tracing system for the analysis of paracrine genetic manipulation while tracing ISC behaviour. Rapport tracing reveals that Ecdysone-induced Crol controls mitogenic Wnt/Wg-ligand expression from epithelial enterocytes activating ISC mitosis. Paracrine Wg stimulation is counterbalanced by Crol-repression of string/CDC25 and CyclinB autonomously in ISC. Rapport-based ISC tumours confirm paracrine stimulation through the Ecdysone-Crol-Wg axis on mitotic behaviour, whereas the autonomous anti-proliferative role of Crol in ISC is conserved in models of colorectal cancer. Finally, mathematical modelling corroborates increasing enterocyte numbers and Wnt/Wg-degradation to set a stable post-mating intestinal size. Together, our findings provide insights into the complex endocrine growth control mechanisms during mating-induced adaptations and might help untangling pleiotropic hormonal effects observed in gastrointestinal tumorigenesis.