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Abstract

Suggestive evidence points that exogenous exposure to steroid hormones has detrimental consequences that are not well explored specifically in the gut, where nutrient uptake occurs. The human gastrointestinal (GI) tract expresses endogenous steroid hormone receptors in the crypts and the enterocytes but their functions are not well understood. Accumulating epidemiological data suggest that GI tumor progression in most cases maybe endocrine dependent. Given the complexity of the mammalian gut yet, the genetic amenability of cell-type specific gene manipulation in Drosophila melanogaster, I studied the effect of exogenously fed or endogenous steroid hormone signaling on the gut and its implications during homeostasis and disease. In this PhD thesis, I discover the gut to be a sexually dimorphic organ that is regulated by steroid sex hormone: 20-hydroxyecdysone (20HE), which binds EcRUsp receptor complex and activates downstream target gene transcription during aging and after mating, but not after stress (the receptors have non-overlapping functions). 20HE stimulates intestinal stem cell (ISC) division in a biphasic manner when fed for 16-20hrs, with males being insensitive to the 1st peak and both sexes competent to divide at the 2nd peak of ISC division. EcR functions in the ISCs cell autonomously and in enteroblasts (EBs) non-autonomously to regulate the ISC division. Females have higher levels of circulating 20HE than the males and I identified the ovaries as an endogenous ecdysone source to control mating-induced ecdysone-dependent ISC mitoses and post-matingdependent gut growth to promote optimal egg-laying. This reproductive advantage given by the highly active female gut comes at the expense of a faster aging epithelium and higher propensity to tumors. Interestingly, exogenous 20HE feeding to males overrides the restricted ability of male ISCs to divide and abolishes the sex differences in ISC division accompanied by transcriptional regulation of metabolic and cell-cycle related genes and subsequent gut growth. All in all, this study identifies sexually dimorphic 20HE levels as a regulator of ISC behavior and intestinal growth at the expense of gut deterioration and aging.