Forward and feedback regulation of cyclic steroid production in Drosophila melanogaster

Abstract

In most animals, steroid hormones are crucial regulators of physiology and developmental life transitions. Steroid synthesis depends on extrinsic parameters and autoregulatory processes to fine-tune the dynamics of hormone production. In Drosophila, transient increases of the steroid prohormone ecdysone, produced at each larval stage, are necessary to trigger moulting and metamorphosis. Binding of the active ecdysone (20-hydroxyecdysone) to its receptor (EcR) is followed by the sequential expression of the nuclear receptors E75, DHR3 and βFtz-f1, representing a model for steroid hormone signalling. Here, we have combined genetic and imaging approaches to investigate the precise role of this signalling cascade within theprothoracic gland (PG), where ecdysone synthesis takes place. We show that these receptors operate through an apparent unconventional hierarchy in the PG to control ecdysone biosynthesis. At metamorphosis onset, DHR3 emerges as the downstream component that represses steroidogenic enzymes and requires an early effect of EcR for this repression. To avoid premature repression of steroidogenesis, E75 counteracts DHR3 activity, whereas EcR and βFtz-f1 act early in development through a forward process to moderate DHR3 levels. Our findings suggest that within the steroidogenic tissue, a given 20-hydroxyecdysone peak induces autoregulatory processes to sharpen ecdysone production and to confer competence for ecdysteroid biosynthesis at the next developmental phase, providing novel insights into steroid hormone kinetics.

Nuclear receptor ecdysone‐induced protein 75 is required for larval–pupal metamorphosis in the Colorado potato beetle Leptinotarsa decemlineata (Say)

“…In D . melanogaster , Dm E75B binds to Dm HR3 (Reinking et al ., ; Palanker et al ., ) in a NO‐dependent manner (Cáceres et al ., ) to regulate ecdysteroidogenesis (Parvy et al ., ). The expression profiles suggest the conserved functions in ecdysteroidogenesis regulation of the three LdE75 s in L. decemlineata .…”

“…In D . melanogaster , feeding 20E rescued a developmental defect in E75 RNAi larvae (Parvy et al ., ). All of these results demonstrate that E75 knockdown leads to 20E deficiency.…”

“…Therefore, the small 20E rise in the fourth‐instar L. decemlineata larvae seems to be tightly regulated, mainly by Ld E75 and Ld HR3, similar to the regulation of the major 20E pulse in the final larval instar in D . melanogaster (White et al ., ; Cáceres et al ., ; Parvy et al ., ).…”

Conserved and Exapted Functions of Nuclear Receptors in Animal Development

“…It is essential for larval development, responding to ecdysone regulatory pathways at the onset of metamorphosis [19]. E75 is required for ecdysteroid biosynthesis in the prothoracic gland, and it counteracts DHR3 to avoid the premature repression of steroidogenesis [20]. Germline clones of E75 mutations cause germline arrest prior to meiosis entry, and degeneration of oocytes with follicle cell migration defects [21,22].…”

Stimulation of orphan nuclear receptor HR38 gene expression by PTTH in prothoracic glands of the silkworm, Bombyx mori

“…More recently, it was shown that EcR-dependent positive feedback operating downstream of PTTH signaling plays a critical role in generating the high-level pulse that triggers pupariation in response to PTTH (Moeller et al, 2013). Complex interaction among the NRs, EcR, E75, DHR3, and bFTZ-F1, which mediate ecdysone signaling (King-Jones and Thummel, 2005), appears to be involved in regulating ecdysteroidogenesis (Parvy et al, 2014). Although those studies clearly indicated the involvement of the NRs in regulating ecdysteroidogenesis, the link from PTTH signaling to the NRs is not very clear.…”