Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Sex-specific steroid hormones control cell growth and proliferation in reproductive organs including the ovaries, breast, uterus, prostate and testes. But how they impact non-reproductive organs is less well known. Considering the sex-biased incidence of many common diseases (e.g. colorectal and gastric cancer), the physiological effects of steroid signaling on the non-sex organs probably have profound health-relevance. We discovered that the Drosophila steroid hormone, 20-hydroxy-ecdysone (20HE), promotes intestinal stem cell (ISC) proliferation and adaptive organ growth, causing the female fly’s intestine to nearly double in size after mating (4). 20HE is produced by the activated ovaries after mating, and stimulates ISC proliferation via its receptor EcR/Usp and downstream targets Broad and Eip75B. 20HE also triggers EGFR/ERK signaling via unknown mechanisms, and this is essential for ISC activation. Our data suggest that 20HE-dependent gut remodeling in females enhances nutrient uptake, fecundity and reproductive fitness. However, the 20HE-dependent hyperactivity of ISCs also increases the female predisposition to gut dysplasia and tumorigenesis, a fitness trade off that can shorten lifespan. Our findings raise many questions about how 20HE signaling re-configures the female gut, how this alters gut and whole-body physiology, and whether sex steroids play similar roles in mammals. Here we address these questions in four Specific Aims. First, we use cell type-targeted genetics to determine the functions of EcR signaling in ISCs and committed progenitors called enteroblasts (EB), focusing on how 20HE gene targets activate ISC growth, metabolism and division, and on how 20HE amplifies the stem cell pool. In Aim 2, we use single cell RNA sequencing to map the effects of 20HE on each of the five main gut cell types in vivo. We also perform in vivo EcR binding site analysis by CUT&Tag, to map direct 20HE:EcR gene targets in midgut progenitor cells. The combined data from these assays will give a comprehensive atlas of the gene expression network effects of 20HE signaling in the gut. In Aim 3 we test the hypothesis that 20HE optimizes nutrient delivery to the fly’s other organs (e.g. ovaries, fat body) by altering the growth, metabolism and/or digestive capabilities of gut enterocytes. In Aim 4, we conduct experiments in mouse intestinal organoids and mice, testing whether the human sex steroids estradiol, progesterone, and/or testosterone promote intestinal epithelial cell (IEC) proliferation and gut growth in mammals. These studies will provide insights into the action of sex steroids as mitogens, regulators of stem cell self-renewal, and mediators of metabolism and nutrient uptake. This work will provide paradigms and lead data for understanding the basis of the sex-biased incidence of many human diseases, notably those involving altered stem cell behavior such as cancer, chronic inflammation, degenerative, and metabolic diseases.
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