Control of target gene specificity during metamorphosis by the steroid response gene E93

Abstract

Hormonal control of sexual maturation is a common feature in animal development. A particularly dramatic example is the metamorphosis of insects, in which pulses of the steroid hormone ecdysone drive the wholesale transformation of the larva into an adult. The mechanisms responsible for this transformation are not well understood. Work in Drosophila indicates that the larval and adult forms are patterned by the same underlying sets of developmental regulators, but it is not understood how the same regulators pattern two distinct forms. Recent studies indicate that this ability is facilitated by a global change in the responsiveness of target genes during metamorphosis. Here we show that this shift is controlled in part by the ecdysone-induced transcription factor E93. Although long considered a dedicated regulator of larval cell death, we find that E93 is expressed widely in adult cells at the pupal stage and is required for many patterning processes at this time. To understand the role of E93 in adult patterning, we focused on a simple E93-dependent process, the induction of the Dll gene within bract cells of the pupal leg by EGF receptor signaling. In this system, we show that E93 functions to cause Dll to become responsive to EGF receptor signaling. We demonstrate that E93 is both necessary and sufficient for directing this switch. E93 likely controls the responsiveness of many other target genes because it is required broadly for patterning during metamorphosis. The wide conservation of E93 orthologs suggests that similar mechanisms control life-cycle transitions in other organisms, including vertebrates.Distal-less | Eip93F | epidermal growth factor receptor | ultraspiracle | heterochrony S teroid hormones control metabolism, reproduction, and development in many organisms and have been linked to numerous human health problems. Steroids often control major transitions in the life cycle, regulating distinct cell responses in a stage-specific manner. Despite their global importance in development, relatively little is known about how steroid hormones control such stage-specific responses. One of the most dramatic life-cycle transitions driven by steroids is the metamorphosis of insects, in which there is a wholesale transformation of the larva into the adult. In Drosophila, metamorphosis is triggered by pulses of the steroid hormone 20-OH ecdysone (ecdysone) (reviewed in refs. 1-4). A complex of ecdysone bound to its nuclear receptor, a heterodimer of the ecdysone receptor (EcR) and the RXR ortholog Ultraspiracle (Usp), directly activates a small number of primary response genes, including E93, which in turn regulate many secondary response genes that function more directly in controlling cell fate. The role of ecdysone signaling in early events of metamorphosis, such as the death of larval cells and the morphogenesis of adult structures, has been studied extensively. However, mechanisms underlying the control of adult cell fates by ecdysone have been poorly characterized.In adult cells, many genes seem to un...

Transcription factor E93 specifies adult metamorphosis in hemimetabolous and holometabolous insects

“…Finally, we have found that the role of E93 is also conserved in the highly derived holometabolous insect D. melanogaster. Although first identified as a specific regulator of cell death during the prepupal stage (13,14), DE93 has recently been found to be a more general temporal regulator of gene expression during the metamorphosis of the fly (25,26). Consistent with its role as adult specifier, we observed that DE93 expression is restricted to the metamorphic prepupal and pupal stages ( Fig.…”

Genetic Control of Specificity to Steroid-Triggered Responses in Drosophila

“…Our data also suggest that PSG mutations may represent unique alleles of their respective genes. For example, E93 psg11 complements the E93 1 allele but fails to complement the E93 vno allele, even though both lethal mutations map to the same gene (Mou et al 2012). A similar allelespecific phenotype was recently described for bel psg9 , which disrupts a subset of molecular functions regulated by belle (Ihry et al 2012).…”

“…In fact, one of the best-characterized stage-specific targets of ecdysone is E93 (Baehrecke and Thummel 1995; Lee et al 2000). E93 is an ecdysone primary response gene, directly induced by the prepupal pulse of ecdysone, and thought to provide specificity to ecdysone responses (Lee et al 2000;Mou et al 2012). To determine whether the remaining PSG genes were also targets of ecdysone, we first tested whether ecdysone was required for expression of these genes.…”

Molecular mechanism underlying juvenile hormone-mediated repression of precocious larval–adult metamorphosis

“…Given that both BmE93 isoforms share a common ORF and are involved in programmed cell death, it is likely that BmE93A and BmE93B function to disrupt larval and pupal traits in larval-pupal and pupal-adult metamorphosis, respectively. Additionally, in D. melanogaster, E93 is expressed widely in adult cells during the pupal stage and contributes to many patterning processes at the adult stage (44), suggesting that BmE93B might be required for the patterning process in B. mori.…”