Ecdysone exerts biphasic control of regenerative signaling, coordinating the completion of regeneration with developmental progression

Abstract

In Drosophila melanogaster, loss of regenerative capacity in wing imaginal discs coincides with an increase in systemic levels of the steroid hormone ecdysone, a key coordinator of their developmental progression. Regenerating discs release the relaxin hormone Dilp8 (Drosophila insulin-like peptide 8) to limit ecdysone synthesis and extend the regenerative period. Here, we describe how regenerating tissues produce a biphasic response to ecdysone levels: lower concentrations of ecdysone promote local and systemic regenerative signaling, whereas higher concentrations suppress regeneration through the expression of broad splice isoforms. Ecdysone also promotes the expression of wingless during both regeneration and normal development through a distinct regulatory pathway. This dual role for ecdysone explains how regeneration can still be completed successfully in dilp8−mutant larvae: higher ecdysone levels increase the regenerative activity of tissues, allowing regeneration to reach completion in a shorter time. From these observations, we propose that ecdysone hormone signaling functions to coordinate regeneration with developmental progression.

Local ecdysone synthesis in a wounded epithelium sustains developmental delay and promotes regeneration inDrosophila

“…How Ec is concentrated locally in these two scenarios is unclear, but could rely on secretion, uptake, or local sequestration, perhaps including low levels of Ec produced by the PG during the developmental pause. EcR activity has also been shown to be induced within larval wing discs damaged by exposure to gamma irradiation (Karanja et al, 2022), which parallels the effect of rn>rpr ts and egr ts observed in this study. However, the source of Ec following irradiation was not examined.…”

“…Given the pro-growth Ec role in discs (Dye et al, 2017, Herboso et al, 2015, Karanja et al, 2022, Gokhale et al, 2016, Nogueira Alves et al, 2022), we assessed effects of pthm KD and Cyp18a1 KD on cell division within the blastema, focusing on R48 when 7xEcRE-GFP activity is most dependent on pthm (see Fig. 2 ).…”

“…This temporal correlation has led to the hypothesis that high Ec inhibits regeneration (Narbonne-Reveau and Maurange, 2019). However, Ec can promote regeneration in other species and is present during regeneration-competent stages of the Drosophila life cycle at lower levels that promote growth in the absence of injury (Das and Durica, 2013, Dye et al, 2017, Herboso et al, 2015, Karanja et al, 2022). Moreover, Ec/EcR are required for activity of the Dpp and Wg pathways (Parker and Struhl, 2020), which promote normal and regenerative wing disc growth.…”

E93 controls adult differentiation by repressingbroadinDrosophila

“…Our findings, along with others (11, 22), strongly indicate that the regenerative capacity of damaged wing larval cells is contingent upon an environment lacking Br, thereby sustaining wing cells in a differentiation-refractory state. Indeed, it has been demonstrated that the wg 1 enhancer is activated in wing disc cells upon tissue injury, contributing to wing regeneration (25, 37), and further, this enhancer is repressed by Br in a context of tissue damage (38).…”

Interorgan communication through peripherally derived peptide hormones inDrosophila

“…Lgr3 is also required in the PG itself for regulating ecdysone production during regeneration [ 56 ]. Notably, the lower concentrations of ecdysone, suppressed by Dilp8, effectively promote regenerative activity in damaged imaginal disks, whereas higher concentrations suppress regeneration [ 57 ] ( Figure 1a ). This peripheral tissue-CNS interaction is a typical mechanism to ensure developmental robustness in multicellular organisms, as it secures enough time for regenerating damaged imaginal disks before pupariation.…”