The Insect Neuropeptide PTTH Activates Receptor Tyrosine Kinase Torso to Initiate Metamorphosis

Rewitz, Kim; Yamanaka, Naoaki; Gilbert, Lawrence I.; O’Connor, Michael B.

doi:10.1126/science.1176450

Cited by 325 publications

(427 citation statements)

References 20 publications

(32 reference statements)

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“…On the other hand, sickle↓ and hid↓ (apoptosis effectors) failed to rescue the L3 arrest phenotype. In addition, upregulating the receptor that triggers ecdysone synthesis, Torso, 28 or upregulating the early effectors of ecdysone signaling, Br-C genes, 24 also failed to bypass the deleterious EcR or USP downregulation ( Figure 4b). This is consistent with the lack of ecdysteroid synthesis in experimental larvae shown by direct measurements above (Figure 2b).…”

Section: After Tool Validation (Supplementary Data and Supplementarymentioning

confidence: 99%

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: After Tool Validation (Supplementary Data and Supplementarymentioning

confidence: 99%

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

2015

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“…It might be notable here that DHR3 has recently been shown to have an unexpected role as a regulator of cell-autonomous growth through S6 kinase (Montagne et al 2010). Alternatively, in the absence of NOS, PTTH might continue to signal through the Torso/ERK pathway (Rewitz et al 2009), leading to extra endoreplication cycles in the PG cells (Ghosh et al 2010). Double knockdown of various components in the PG-for example, NOS and torso-will help establish the epistatic relationship of these various signaling pathways that contribute to PG size control.…”

Section: No-e75 Interaction-beyond Regulation Of Bftz-f1 Expressionmentioning

confidence: 99%

Nitric oxide directly regulates gene expression during Drosophila development: need some gas to drive into metamorphosis?: Figure 1.

Yamanaka

O’Connor

2011

Genes Dev.

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Nitric oxide (NO) is an important second messenger involved in numerous biological processes, but how it regulates gene expression is not well understood. In this issue of Genes & Development, Cáceres and colleagues (pp. 1476–1485) report a critical requirement of NO as a direct regulator of gene expression through its binding to a heme-containing nuclear receptor in Drosophila. This may be an anciently evolved mechanism to coordinate behavior and metabolism during animal development.

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“…Work over the past decade has indicated that critical size is regulated by at least two signalling pathways; the insulin/IGF-signalling pathway and the PTTH/Ras/Rafsignalling pathway [39,[43][44][45][46][47]. Both appear to control the timing of ecdysteroid synthesis by the prothoraric gland and the cessation of growth: insulin/IGF signalling apparently in response to nutritional status [39,44,45]; PTTH/Ras/Raf signalling in response to temporal information [43,46]; and both insulin/IGF and PTTH/Ras/Raf signalling in response to the developmental status of the growing organs [31,[48][49][50]. However, it is unclear whether these or some other pathway mediates the effects of temperature on critical size.…”

Section: (A) Regulation Of Critical Sizementioning

confidence: 99%

Temperature-size rule is mediated by thermal plasticity of critical size inDrosophila melanogaster

2013

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Most ectotherms show an inverse relationship between developmental temperature and body size, a phenomenon known as the temperature-size rule (TSR). Several competing hypotheses have been proposed to explain its occurrence. According to one set of views, the TSR results from inevitable biophysical effects of temperature on the rates of growth and differentiation, whereas other views suggest the TSR is an adaptation that can be achieved by a diversity of mechanisms in different taxa. Our data reveal that the fruitfly, Drosophila melanogaster, obeys the TSR using a novel mechanism: reduction in critical size at higher temperatures. In holometabolous insects, attainment of critical size initiates the hormonal cascade that terminates growth, and hence, Drosophila larvae appear to instigate the signal to stop growth at a smaller size at higher temperatures. This is in contrast to findings from another holometabolous insect, Manduca sexta, in which the TSR results from the effect of temperature on the rate and duration of growth. This contrast suggests that there is no single mechanism that accounts for the TSR. Instead, the TSR appears to be an adaptation that is achieved at a proximate level through different mechanisms in different taxa.

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The Insect Neuropeptide PTTH Activates Receptor Tyrosine Kinase Torso to Initiate Metamorphosis

Cited by 325 publications

References 20 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

Nitric oxide directly regulates gene expression during Drosophila development: need some gas to drive into metamorphosis?: Figure 1.

Temperature-size rule is mediated by thermal plasticity of critical size inDrosophila melanogaster

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