Stress response signaling as a metabolic sensor in reproduction

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PROJECT SUMMARY Reproduction is a systemic decision that relies on nutrient availability to support the high energetic cost of gamete production and reproductive behaviors. Disorders that correlate with insufficient or excess body fat mass like anorexia nervosa or polycystic ovarian syndrome are associated with decreased ovulation and infer- tility. In humans and the model organism Drosophila melanogaster, steroid hormones are essential for reproduc- tion, though the molecular cues that relay nutrient information to direct hormonal function are not well understood. In Drosophila, activation of Ecdysone receptor (EcR) by the steroid hormone 20-hydroxyecdysone (20E) is re- quired for oocyte maturation in the ovary. Interestingly, the transcription factor Cryptocephal (Crc), which is in- duced by starvation via the Integrated Stress Response (ISR) pathway, interacts physically with EcR. This study will examine how nutrient sensing alters reproductive capacity via ISR signaling and steroid hormones. I recently found that loss of crc in the fat body (FB), a liver-like and adipose-rich tissue in Drosophila, caused follicle death and decreased lipid/yolk protein composition, defects associated with 20E dysregulation. Additionally, loss of ISR factors caused excess retention of mature oocytes in the ovary. Together, my data suggest that ISR signaling co-regulates oocyte maturation and egg laying behavior. During the training (K99) phase of this award, I will uncover how Crc and EcR link metabolic status to gametogenesis and egg- laying behavior. To this end, I am collaborating with Dr. Kafui Dzirasa at Duke University to adapt a novel neural editing tool for use in Drosophila, creating artificial synapses to characterize regulation of egg laying by the ISR. Starvation, which activates the ISR, attenuates post-mating increases in intestinal function and courtship behavior. During the independent (R00) phase, I will apply the insights and tools acquired during the training phase to identify molecular cues downstream of ISR signaling that control nervous system and gut functions to alter reproductive potential. First, I will determine how the ISR regulates female courtship behavior, which requires inputs from central and peripheral neurons. Next, I will leverage the collaborations forged during the K99 phase to characterize organism-wide expression of EcR- and Crc-responsive reporters under different feeding conditions to interrogate the roles of Crc and EcR in the intestine, where both regulate stem cell dynamics. This will open multiple lines of inquiry into how nutrient sensing controls multiple reproductive events via ISR signaling and inter-organ crosstalk. My proposed studies will develop novel tools and insights that will lay a strong foundation for my independent research program, wherein I will characterize diverse phys- iological consequences of ISR and steroid hormone signaling in metabolic tissues and decipher how this impacts behavior and whole-organism physiology. Ultimately, my work will reveal important insights into how metabolism controls reproduction across organisms, which may lead to novel therapeutics for treating human metabolic disorders that cause sex hormone dysregulation and infertility.