HIF-1α-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development

Growth deceleration before growth termination is a universal feature of growth during development. Transcriptomics analysis reveals that during their two-day period of growth deceleration, wing imaginal discs of Drosophila undergo a progressive metabolic shift from oxidative phosphorylation towards glycolysis. Ultra-sensitive reporters of HIF-1α stability and activity show that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. We confirm the expectation that rising levels of HIF-1α dampen TOR signalling activity through transcriptional activation of REDD1. Conversely, excess TOR leads, in a tissue-size-dependent manner, to hypoxia, which boosts HIF-1α levels and activity. Thus, HIF-1α mediates a negative feedback loop whereby TOR signalling triggers hypoxia, which in turn reduces TOR signalling. Abrogation of this feedback by Sima/HIF-1α knockdown leads to cellular stress, which is alleviated by reduced TOR signalling or a modest increase in environmental oxygen. We conclude that Sima/HIF-1α prevents TOR-mediated growth from depleting local oxygen supplies during normal development.