A role for the Ecdysone receptor in hormonal control of Drosophila melanogaster midgut homeostasis and physiology.

• Applicant: Dr. Tobias Reiff
• Subject Area: Developmental Biology ; Cell Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 411066135

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. Recently, 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. Our preliminary experiments show that intestinal growth upon mating reaches a plateau and that the intestinal size adaptation is partially reversible when males are withdrawn. By a candidate gene approach, we identified the ecdysone steroid hormone receptor (EcR) inhibiting ISC proliferation using our recently developed tracing method 'ReDDM'. We aim to describe ecdysone signaling controlling midgut homeostasis during mating and male withdrawal. Additional preliminary data suggests that early ecdysone response genes E74A and E75B play a role in ISC as well. Furthermore, we will investigate the epistasis of EcR- and JH-signaling cascades that are known to antagonize each other during Drosophila development and investigate downstream effectors on which input from both pathways may converge. Taken together, our preliminary data suggests that the EcR-pathway plays a role in mating related intestinal adaptations in the fruit fly. Interestingly, female mice do not return to their pre-pregnancy weight and intestinal adaptations do not fully regress postpartum, leaving the intestine with higher nutrient resorption capability, possibly playing a role that weight retention. Excessive weight gain and postpartum weight retention are on the rise in western societies, increasing the risk of cardiovascular disease, metabolic syndrome and type II diabetes. By gaining a deeper understanding of pregnancy related intestinal adaptations, our hope is that in the long run treatments can be developed reducing short- and long-term medical complications for future mothers.

• DFG Programme: Research Grants