Zhao, Yifan; (2024) The relationship between growth and oxygen during development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In most instances, growth does not terminate abruptly during development but instead progressively decelerates as tissues and organs approach their final size. Despite the pervasiveness of growth deceleration, its molecular basis remains poorly understood. The author first used transcriptomic profiling to identify genes that correlate or anticorrelate with growth rate in wing precursors (wing discs) of Drosophila third instar (L3) larvae. The gene encoding Lamin C (LamC) was initially considered but further analysis suggested that the decrease in LamC expression observed during growth is unlikely to be a driver of growth deceleration. The author then noted that messenger RNAs (mRNAs) encoding components of aerobic metabolism become increasingly less abundant during wing disc growth, suggesting that discs may become mildly hypoxic. This was confirmed with a purposely designed, highly sensitive reporter of the activity of Similar (Sima)/ hypoxia-inducible factor-1α (HIF-1α), the master regulator of hypoxia response. These results reveal that oxygen becomes limiting as tissue size increases. The author then demonstrate that increased Sima/HIF-1α activity causes a reduction in target of rapamycin (TOR) signalling activity, hence dampening growth. Conversely, excess TOR signalling activity leads to increased hypoxia, as expected since anabolism, or constructive metabolism (one key aspect of growth) indirectly consumes oxygen. Excess TOR signalling activity also causes cellular stress, presumably by putting impossible demands on oxygen supplies. Such TOR-induced stress is exacerbated by sima/HIF-1α knockdown and alleviated by a mild increase in oxygen supply. Thus, the classic hypoxia response mediated by Sima/HIF-1α is deployed during normal growth to ensure that the demands on oxygen imposed by protein synthesis does not exceed the available oxygen supply. Without such a safeguard, tissue stress ensues.

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