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

Abstract

<jats:title>Abstract</jats:title><jats:p>Developmental studies revealed fundamental principles on how organ size and function is achieved, but less is known about organ adaptation to new physiological demands. In fruit flies, juvenile hormone (JH) induces intestinal stem cell (ISC) driven absorptive epithelial expansion balancing energy uptake with increased energy demands of pregnancy. Here, we show 20-Hydroxy-Ecdysone (20HE)-signaling controlling organ homeostasis with physiological and pathological implications. Upon mating, 20HE titer in ovaries and hemolymph are increased and act on nearby midgut progenitors inducing <jats:italic>Ecdysone-induced-protein-75B (Eip75B)</jats:italic>. Strikingly, the <jats:italic>PPARγ</jats:italic>-homologue <jats:italic>Eip75B</jats:italic> drives ISC daughter cells towards absorptive enterocyte lineage ensuring epithelial growth. To our knowledge, this is the first time a systemic hormone is shown to direct local stem cell fate decisions. Given the protective, but mechanistically unclear role of steroid hormones in female colorectal cancer patients, our findings suggest a tumor-suppressive role for steroidal signaling by promoting postmitotic fate when local signaling is deteriorated.</jats:p>

Steroid‐dependent switch of OvoL/Shavenbaby controls self‐renewal versus differentiation of intestinal stem cells

“…Two contemporary studies confirm the role of ecdysone in sustaining stemness and undifferentiated state of Drosophila ISCs in the midgut. Both studies demonstrate that EcR and its cofactor Usp foster division and expansion of ISCs in response to a peak of steroids synthesized in ovaries upon mating (Ahmed et al , 2020; Zipper et al , 2020). These data provide compelling evidence for ovary‐to‐gut communication and show that sex hormones remodel stem cell fate to adjust organ size, as means to face elevated energetic costs imposed by reproduction.…”

“…Results from a large in vivo screen reveal that svb enhancers are directly regulated on the one hand by Wnt and EGFR local signaling for ISC/EB survival and self‐renewal, and, on the other hand, by intrinsic regulatory factor Pdm1 for EC differentiation. Moreover, recent studies show that the systemic steroid hormone ecdysone, which is produced in ovaries (Uryu et al , 2015), increases proliferation and regulates the fate of stem cells in the intestine (Ahmed et al , 2020; Zipper et al , 2020). Our data suggest that these effects of ecdysone are due, at least in part, to the activation of pri expression that triggers, in turn, Svb processing.…”

Sensitive High-Throughput Assays for Tumour Burden Reveal the Response of a Drosophila melanogaster Model of Colorectal Cancer to Standard Chemotherapies

“…In contrast, ApcRas clones disappear over time, with the few that survive forming tumour-like overgrowths ( Figure 1 a and Figure 2 a and [ 19 ]). Until recently, we quantified tumour burden by imaging each midgut, stitching the images together manually (midguts can be up to 6mm long [ 27 , 28 ]), and then used standard functions on Fiji to outline and calculate the area of each clone. While this method provides highly accurate parameters to describe the behaviour of clones, it is extremely laborious and can also introduce user bias.…”

Sensitive high-throughput assays for tumour burden reveal the response of aDrosophila melanogastermodel of colorectal cancer to standard chemotherapies

“…1a, 2a and 19 ). Until recently, we quantified tumour burden by imaging each midgut, stitching the images together manually (midguts can be up to 6mm long 28,29 ), and then used standard functions on Fiji to outline and calculate the area of each clone. While this method provides highly accurate parameters to describe the behaviour of clones, it is extremely laborious and can also introduce user bias.…”