Hypoxia couples growth and developmental timing by decoupling steroid synthesis and secretion

In almost all animals, low physiological levels of oxygen (hypoxia) reduce growth rate and adult body size. Despite the near ubiquity of this response, the systemic mechanisms that coordinate growth and development under hypoxia remain poorly understood. In Drosophila, hypoxia increases circulating levels of the steroid hormone ecdysone to inhibit insulin/IGF signaling and slow growth. At the same time, ecdysone biosynthesis is reduced to delay pupation and extend development. Traditionally, the secretion of lipid-soluble steroids is thought to be regulated at the level of biosynthesis. This therefore presents a paradox: how can a single environmental factor both increase ecdysone levels yet decrease ecdysone synthesis? Our data show that this paradox is resolved by the dual regulation of ecdysone at the levels of secretion and biosynthesis. We show that, in the short term, hypoxia increases basal levels of ecdysone via vesicle-mediated steroid hormone secretion, while in the long term, hypoxia decreases the expression of genes involved in ecdysone synthesis to delay the ecdysone peak that triggers pupation. We also present evidence that both ecdysone synthesis and secretion are regulated, in part, by NO-signaling. Collectively, our findings reveal that regulated steroid secretion as a critical and environmentally-responsive component of endocrine control, expanding our understanding of how animals integrate growth and developmental timing in response to acute and chronic environmental change. Author SummaryLow oxygen levels (hypoxia) slow growth and development in almost all animals, but how changes in oxygen in the environment are sensed and turned into body-wide hormonal signals is still not well understood. Using Drosophila, we show that oxygen regulates the steroid hormone ecdysone to slow growth and development through two distinct mechanisms: fast hormone release and slower suppression of hormone synthesis. In the short-term, low oxygen triggers the active release of stored ecdysone from the gland that produces it, leading to a rise in circulating hormonal levels that slows body growth. In the longer-term, low oxygen reduces ecdysone production, delaying the hormone peak that initiates pupation and extending overall development. While it is widely accepted that fat-soluble steroids can pass freely, and passively, across membranes, these findings suggest that their active release allows a rapid response to environmental change. More broadly, our work suggests that environmental modulation of steroid secretion, alongside steroid synthesis, may represent a general strategy by which animals coordinate short- and long-term developmental responses to environmental stress.