Growth-induced physiological hypoxia correlates with growth deceleration during normal development

Abstract

Growth deceleration is a universal feature of growth during development: most organs and tissues slow down their growth rate much before growth termination. 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 an ultra-sensitive reporter HIF-1 activity, which reveals that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. Growth is energetically expensive and thus expected to contribute, indirectly, to oxygen consumption. Indeed, excess TOR signalling, a key stimulator of growth, triggers hypoxia locally and systemically, highlighting the need to rein in growth when oxygen becomes limiting. This is achieved by a negative feedback loop whereby the classic TOR-inhibitory function of HIF-1 is deployed in response to developmental hypoxia. The absence of Sima/HIF-1 leads to cellular stress, which is alleviated by reduced TOR signalling. Conversely, a small increase in oxygen supply reduces the stress induced by excess TOR activity. We conclude that mild hypoxia is a normal feature of organ development and that Sima/HIF-1 prevents growth-induced oxygen demand from exceeding supply.