A Novel Ecdysone Receptor Mediates Steroid-Regulated Developmental Events during the Mid-Third Instar of Drosophila

Costantino, Benjamin F. B.; Bricker, Daniel K.; Alexandre, Kelly M.; Shen, Kate; Merriam, John R.; Antoniewski, Christophe; Callender, Jenna L.; Henrich, Vincent C.; Presente, Asaf; Andres, Andrew J.

doi:10.1371/journal.pgen.1000102

Cited by 94 publications

(90 citation statements)

References 65 publications

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“…45 These proposals would be in line with another study showing that silencing USP in the salivary gland does not block glue protein synthesis but it requires EcR. 46 Yet, the binding of ecdysone to a receptor, other than the heterodimer EcR/USP, remained to be proven.…”

Section: Discussionmentioning

confidence: 67%

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

2015

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The active form of the Drosophila steroid hormone ecdysone, 20-hydroxyecdysone (20E), binds the heterodimer EcR/USP nuclear receptor to regulate target genes that elicit proliferation, cell death and differentiation during insect development. Although the 20E effects are relatively well known, the physiological relevance of its receptors remains poorly understood. We show here that the prothoracic gland (PG), the major steroid-producing organ of insect larvae, requires EcR and USP to survive in a critical period previous to metamorphosis, and that this requirement is 20E-independent. The cell death induced by the downregulation of these receptors involves the activation of the JNK-encoding basket gene and it can be rescued by upregulating EcR isoforms which are unable to respond to 20E. Also, while PG cell death prevents ecdysone production, blocking hormone synthesis or secretion in normal PG does not lead to cell death, demonstrating further the ecdysone-independent nature of the receptor-deprivation cell death. In contrast to PG cells, wing disc or salivary glands cells do not require these receptors for survival, revealing their cell and developmental time specificity. Exploring the potential use of this feature of steroid receptors in cancer, we assayed tumor overgrowth induced by altered yorkie signaling. This overgrowth is suppressed by EcR downregulation in PG, but not in wing disc, cells. The mechanism of all these cell death features is based on the transcriptional regulation of reaper. These novel and context-dependent functional properties for EcR and USP receptors may help to understand the heterogeneous responses to steroid-based therapies in human pathologies. Steroid hormones control multiple biological processes and, consequently, their faulty regulation underlies many pathologies. 1,2 The main Drosophila steroid hormone, ecdysone, is synthesized in the larval prothoracic gland (PG) using dietary sterols and cytochrome P450 enzymes. 3 Following its pulsated secretion into the hemolymph, peripheral tissues convert ecdysone into biologically active 20-hydroxyecdysone (20E) to control larval molting and metamorphosis. 4 The 20E signal is transduced by heterodimers of two nuclear receptors, ecdysone receptor (EcR) and Ultraspiracle (USP). 5 USP exhibits a single form throughout development. By contrast, EcR encodes three protein isoforms (EcRA, EcRB1 and EcRB2). These show common DNA-and hormone-binding domains but different N-termini although all of them can heterodimerize USP. 6,7 Each EcR isoform is hypothesized to have specific functions based on their distinct spatial and temporal patterns and N-termini. [8][9][10] EcR and USP DNA-binding domains recognize ecdysone response sequences which are short palindromes. 11 Like its vertebrate counterparts, 12 the ligand-EcR/USP complex activates transcription, whereas the unliganded receptor act as a repressor. [13][14][15] The in vivo validation of repressor activities for unliganded complexes, however, is mostly indirect. For example, EcR or USP loss...

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Section: Discussionmentioning

confidence: 67%

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

2015

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“…P{GawB}AB1-Gal4 is an enhancer trap element that displays constitutive expression of GAL4 in larval salivary glands. 27 …”

Section: Methodsmentioning

confidence: 99%

The Garz Sec7 domain guanine nucleotide exchange factor for Arf regulates salivary gland development in Drosophila

Szul¹,

Burgess

Jeon

et al. 2011

Cellular Logistics

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“…sg-Gal4; Sgs3-GFP was a gift from Andrew J. Andres (Costantino et al, 2008). The let-7-Cp 12.5kb :: LacZ, ::LacZ, let-7-Cp 3.3kb ::LacZ, let-7-Cp 3.3kbEcRE1-3 ::LacZ, let-7-Cp 3.3kb ::cDNA, and let-7-Cp 3.3kbEcRE1-3 :: cDNA transgenes were inserted into the PBac{y[+]-attP-3B}VK00033 landing site by Rainbow Transgenic Services (CA, USA).…”

Section: Uas-ecr-rnai Uas-ecra-w650a Uas-ecra Uas-ecrb1mentioning

confidence: 99%

“…Dominant-negative (EcR-DN) and RNAi (EcR-RNAi) UAS transgenes targeting EcR were expressed in larval salivary glands using the salivary gland Gal4 driver (sgGal4) (Costantino et al, 2008), and semi-quantitative RT-PCR was performed to determine levels of pri-let-7-C in -18 hours, -8 hours, -4 hours and 0 hour APF RNA samples. Expression of EcR-DN or EcR-RNAi greatly diminished pri-let-7-C levels in third larval instar salivary glands (Fig.…”

Section: Ecr Signaling Is Required For Let-7-c Expressionmentioning

confidence: 99%

Hormonal activation of let-7-C microRNAs via EcR is required for adult Drosophila melanogaster morphology and function

Chawla

Sokol

2012

Development

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Steroid hormones and their nuclear receptors drive developmental transitions in diverse organisms, including mammals. In this study, we show that the Drosophila steroid hormone 20-hydroxyecdysone (20E) and its nuclear receptor directly activate transcription of the evolutionarily conserved let-7-complex (let-7-C) locus, which encodes the co-transcribed microRNAs miR-100, let-7 and miR-125. These small RNAs post-transcriptionally regulate the expression of target genes, and are required for the remodeling of the Drosophila neuromusculature during the larval-to-adult transition. Deletion of three 20E responsive elements located in the let-7-C locus results in reduced levels of let-7-C microRNAs, leading to neuromuscular and behavioral defects in adults. Given the evolutionary conservation of let-7-C microRNA sequences and temporal expression profiles, these findings indicate that steroid hormone-coupled control of let-7-C microRNAs is part of an ancestral pathway controlling the transition from larval-to-reproductive animal forms.

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A Novel Ecdysone Receptor Mediates Steroid-Regulated Developmental Events during the Mid-Third Instar of Drosophila

Cited by 94 publications

References 65 publications

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

Ligand-independent requirements of steroid receptors EcR and USP for cell survival

The Garz Sec7 domain guanine nucleotide exchange factor for Arf regulates salivary gland development in Drosophila

Hormonal activation of let-7-C microRNAs via EcR is required for adult Drosophila melanogaster morphology and function

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