Metabolic shifts during growth deceleration in Drosophila imaginal wing discs

Growth during development is often characterised by progressive deceleration, as organisms, tissues, and organs approach their final size. Using transcriptomics analysis, we show that, during their two-day period of growth deceleration, wing imaginal discs of Drosophila undergo a progressive metabolic shift away from oxidative phosphorylation and towards glycolysis. We then develop a sensitive reporter of HIF-1a activity (a proxy for hypoxia), which allows us to show that imaginal discs become mildly, though increasingly, hypoxic during normal development, in normoxic conditions. As a result, HIF-1a dampens growth via transcriptional activation of scylla/REDD1, a negative regulator of TOR signalling. We find that overactivation of TOR signalling triggers a marked hypoxia response both cell-autonomously and in surrounding tissues. This suggests that, in wildtype animals, TOR activity imposes increasing pressure on oxygen supplies. Indeed, in the absence of HIF-1a, TOR signalling triggers JNK signalling, a marker of cellular stress. Moreover, TOR-induced stress is alleviated by a small increase is oxygen supplies. Our results suggest that, during normal development, Sima/HIF-1a prevents growth-induced demand from exceeding available supplies, which become increasing scarce as tissue size increases. Overall design: We performed bulk RNA-Sequencing (RNA-Seq) on precisely timed third larval instar (L3) wing imaginal discs at seven developmental time points, ranging from 80 to 118 hours after egg laying (AEL). For each time point, three biological replicates and two technical replicates were included.