The steroid hormone ecdysone regulates growth rate in response to oxygen availability

Abstract

In almost all animals, physiologically low oxygen (hypoxia) during development slows growth and reduces adult body size. The developmental mechanisms that determine growth under hypoxic conditions are, however, poorly understood. Here we show that the growth and body size response to moderate hypoxia (10% O2) in Drosophila melanogaster is systemically regulated via the steroid hormone ecdysone. Hypoxia increases level of circulating ecdysone and inhibition of ecdysone synthesis ameliorates the negative effect of low oxygen on growth. We also show that the effect of ecdysone on growth under hypoxia is through suppression of the insulin/IGF-signaling pathway, via increased expression of the insulin-binding protein Imp-L2. These data indicate that growth suppression in hypoxic Drosophila larvae is accomplished by a systemic endocrine mechanism that overlaps with the mechanism that slows growth at low nutrition. This suggests the existence of growth-regulatory mechanisms that respond to general environmental perturbation rather than individual environmental factors.

Hypoxia delays steroid-induced developmental maturation in Drosophila by suppressing EGF signaling

“…Our results are similar to a previous report that examined the effects of moderate hypoxia (10% oxygen) and showed that hypoxia exposure delayed the maturation-inducing ecdysone pulse at the end of the larval period [ 46 ]. Interestingly this study also found that hypoxia exposure early in the third instar led to elevated hemolymph ecdysone titers and a subsequent study reported that this elevated ecdysone signaling led to reduced body growth by inducing expression of ImpL2, a negative regulator of systemic insulin signaling [ 47 ]. These results suggest that hypoxia exposure may have different effects on ecdysone depending on the stage of larval development.…”

“…The delayed attainment of CW caused by hypoxia exposure in early larval development is most likely due to a similar lowering of systemic insulin/TOR. For example, hypoxia has been shown to promote HIF-1-alpha-independent inhibition of TOR signaling [ 49 , 50 ], suppress systemic insulin signaling by reducing insulin secretion from the brain [ 48 , 49 ], and upregulate expression of the insulin antagonist, ImpL2 [ 47 ]. These suppressive effects of hypoxia on insulin/TOR signaling would also persist post CW to reduce late larval growth and hence lead to smaller body size compared to normoxic larvae.…”

Hypoxia delays steroid-induced developmental maturation inDrosophilaby suppressing EGF signaling

“…CW is determined, in large part, by an animal's growth rate, which in Drosophila larvae is controlled by the conserved insulin and TOR kinase signaling pathways (Malita and Rewitz, 2021). Given that hypoxia exposure can suppress larval growth by inhibiting these pathways (Barretto et al, 2020;Kapali et al, 2022;Lee et al, 2019;Texada et al, 2019;Wong et al, 2014), it is possible that the delay in maturation merely reflects a hypoxia-induced delay in attainment of CW. To address this, we raised larvae from hatching in either normoxia or hypoxia and then at defined times in development we switched them to starvation conditions and monitored their subsequent development in normoxia.…”

“…The 10 delayed attainment of CW caused by hypoxia exposure in early larval development is most likely due to a similar lowering of systemic insulin/TOR. For example, hypoxia has been shown to promote HIF-1-alpha-independent inhibition of TOR signaling (Lee et al, 2019;Texada et al, 2019), suppress systemic insulin signaling by reducing insulin secretion from the brain (Texada et al, 2019;Wong et al, 2014), and upregulate expression of the insulin antagonist, ImpL2 (Kapali et al, 2022).…”

“…When grown in moderate hypoxia (5-10% oxygen) larvae slow their growth rate and delay their maturation leading to smaller sized adults (Callier et al, 2015;Callier and Nijhout, 2014;Callier et al, 2013;Farzin et al, 2014;Harrison et al, 2018;Harrison and Haddad, 2011;Kapali et al, 2022;Lee et al, 2019;Peck and Maddrell, 2005;Texada et al, 2019;Wong et al, 2014). Studies have described how the reduction in growth rate occurs through reduced insulin and TOR kinase signaling (Barretto et al, 2020;Kapali et al, 2022;Lee et al, 2019;Texada et al, 2019;Wong et al, 2014). However, the mechanisms by which hypoxia delays the timing of larval maturation remain to be determined.…”