A role for the Ecdysone receptor in hormonal control of Drosophila melanogaster midgut homeostasis and physiology.
Cell Biology
Final Report Abstract
The proper maintenance and size-adaptation of adult organs is crucial to an organisms’ survival and competitivity for reproduction. Adult organs and tissues are fueled by a specialized cell type called adult stem cells (SC). SC are able to self-renew and multipotent, thus are able to generate all different cell types of their given tissue. The process of SC maintaining tissues function and size through constant division and tissue replenishment is called homeostasis, and relies on tight control of stem cell activity. For instance, epithelial damage stimulates SC division rate via local signaling pathways to replenish the tissue and therefore reestablish organ size and integrity. One of the most dramatic physiological adaptations to pregnancy and lactation is an increase in the size of the maternal mammalian intestine. Adaptation of the maternal intestine is a common feature in various taxonomic groups and ensures nutrient uptake during raised energy demand. By the time this proposal was submitted, we revealed that upon mating the release of ‘juvenile hormone’ (JH) from Drosophila melanogaster’s neuroendocrine corpus allatum leads to a larger resorptive surface through the expansion of the midgut epithelium by activating JH-receptors, resulting in intestinal SC (ISC) proliferation. On a broader scope, this finding suggests that adult organs can be remotely adapted by systemic signals to match new physiological conditions. In this research grant, we proposed to investigate the role of the ecdysone steroid hormone receptor (EcR) using our established tracing method ‘ReDDM’, which allowed us to characterize physiological and pathological implications of EcR and its ligand in intestinal homeostasis and tumor pathology. We found that the EcR-ligand 20HE (20-Hydroxy-Ecdysone) is released by the ovaries upon mating and by passing through the hemolymph elicits proliferation of ISC and midgut size adaptations. Importantly, we found that the PPARγ-homologue Ecdysoneinduced-protein-75B (Eip75B) is induced upon mating and drives ISC daughter cells towards absorptive enterocyte lineage which ensures the observed epithelial growth. When we published this data in 2020 in eLife, this finding was the first time a systemic hormone was shown to direct local stem cell fate decisions. Our pathological observations also shed first light into the protective, but mechanistically unclear role of steroid hormones in female colorectal cancer patients and suggest a tumor-suppressive role for steroidal signaling by promoting postmitotic fate when local signaling is deteriorated. Confirming our findings and their importance, Ahmed et al. published similar results on 20HE signalling the same month in "Nature". In addition, results and obtained expertise established during this first DFG grant has been instrumental for many following grants, projects and publications.
Publications
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Ecdysone steroid hormone remote controls intestinal stem cell fate decisions via the PPARγ-homolog Eip75B in Drosophila. eLife, 9.
Zipper, Lisa; Jassmann, Denise; Burgmer, Sofie; Görlich, Bastian & Reiff, Tobias
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The MicroRNA miR-277 Controls Physiology and Pathology of the Adult Drosophila Midgut by Regulating the Expression of Fatty Acid β-Oxidation-Related Genes in Intestinal Stem Cells. Metabolites, 12(4), 315.
Zipper, Lisa; Batchu, Sai; Kaya, Nida Hatice; Antonello, Zeus Andrea & Reiff, Tobias
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Steroid hormone-induced wingless ligands tune female intestinal size in Drosophila. Nature Communications, 16(1).
Zipper, Lisa; Corominas-Murtra, Bernat & Reiff, Tobias
