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• W1994545511 abstract "How steroid hormones shape animal growth remains poorly understood. In Drosophila, the main steroid hormone, ecdysone, limits systemic growth during juvenile development. Here we show that ecdysone controls animal growth rate by specifically acting on the fat body, an organ that retains endocrine and storage functions of the vertebrate liver and fat. We demonstrate that fat body-targeted loss of function of the Ecdysone receptor (EcR) increases dMyc expression and its cellular functions such as ribosome biogenesis. Moreover, changing dMyc levels in this tissue is sufficient to affect animal growth rate. Finally, the growth increase induced by silencing EcR in the fat body is suppressed by cosilencing dMyc. In conclusion, the present work reveals an unexpected function of dMyc in the systemic control of growth in response to steroid hormone signaling. How steroid hormones shape animal growth remains poorly understood. In Drosophila, the main steroid hormone, ecdysone, limits systemic growth during juvenile development. Here we show that ecdysone controls animal growth rate by specifically acting on the fat body, an organ that retains endocrine and storage functions of the vertebrate liver and fat. We demonstrate that fat body-targeted loss of function of the Ecdysone receptor (EcR) increases dMyc expression and its cellular functions such as ribosome biogenesis. Moreover, changing dMyc levels in this tissue is sufficient to affect animal growth rate. Finally, the growth increase induced by silencing EcR in the fat body is suppressed by cosilencing dMyc. In conclusion, the present work reveals an unexpected function of dMyc in the systemic control of growth in response to steroid hormone signaling. The steroid hormone ecdysone acts on Drosophila fat cells to control global growth Upon hormone action, Myc expression in fat cells is repressed Myc controls systemic growth through adipose ribosomal protein content The fat ribosomal content mediates global growth via an unknown relay mechanism Growth is a discontinuous process that needs to be coordinated with the developmental program. In many species, growth is restricted to the juvenile period. Passage into adulthood is accompanied by the acquisition of sexual maturity (maturation) and rapid changes in growth control, leading to a systemic arrest of body growth. The relationships between the onset of maturation and the regulation of growth remain poorly understood. In holometabolous insects, growth and maturation are temporally distinct. Growth is mainly restricted to the larval period and maturation occurs during metamorphosis or pupal development. Tissue growth relies on the insulin/IGF (insulin-like growth factor) signaling pathway (IIS), a highly conserved pathway that couples nutrition with growth. Drosophila has a conserved IIS system with seven insulin-like peptides named Dilps, a unique insulin receptor (dInR), and a conserved cascade of intracellular effectors (Géminard et al., 2006Géminard C. Arquier N. Layalle S. Bourouis M. Slaidina M. Delanoue R. Bjordal M. Ohanna M. Ma M. Colombani J. et al.Control of metabolism and growth through insulin-like peptides in Drosophila.Diabetes. 2006; 55: S5-S8Crossref Scopus (75) Google Scholar). In parallel to the canonical InR pathway, the target of rapamycin (TOR) pathway promotes cell growth through its action on translational initiation, ribosome biogenesis, nutrient storage, endocytosis, and autophagy (reviewed in Arsham and Neufeld, 2006Arsham A.M. Neufeld T.P. Thinking globally and acting locally with TOR.Curr. Opin. Cell Biol. 2006; 18: 589-597Crossref PubMed Scopus (116) Google Scholar, Wullschleger et al., 2006Wullschleger S. Loewith R. Hall M.N. TOR signaling in growth and metabolism.Cell. 2006; 124: 471-484Abstract Full Text Full Text PDF PubMed Scopus (4359) Google Scholar, Guertin and Sabatini, 2007Guertin D.A. Sabatini D.M. Defining the role of mTOR in cancer.Cancer Cell. 2007; 12: 9-22Abstract Full Text Full Text PDF PubMed Scopus (2276) Google Scholar). Multiple molecular crosstalks have been established between the TOR and InR signaling pathways, ensuring that cells integrate both systemic and local cues in their growth program. Other growth inducers have been identified in multicellular organisms, among them the Myc family of transcription factors (reviewed in Eilers and Eisenman, 2008Eilers M. Eisenman R.N. Myc's broad reach.Genes Dev. 2008; 22: 2755-2766Crossref PubMed Scopus (691) Google Scholar). In mammalian cells, activity of the Myc proteins is associated with cell growth and proliferation, inhibition of terminal differentiation, and apoptosis (Grandori et al., 2000Grandori C. Cowley S.M. James L.P. Eisenman R.N. The Myc/Max/Mad network and the transcriptional control of cell behavior.Annu. Rev. Cell Dev. Biol. 2000; 16: 653-699Crossref PubMed Scopus (972) Google Scholar). Consistent with its role in growth control, Myc is a potent regulator of many components of the translation apparatus. It activates RNA polymerase III, rRNA synthesis, ribosome biosynthesis genes, and translation initiation factors. In line with their common action on ribosome biosynthesis and translation initiation, recent data suggest a link between the IIS/TOR network and Myc. In specific tissues, expression of the Drosophila Myc ortholog dMyc is repressed by dFoxO, a transcription factor that is inhibited by the activation of IIS. In addition, TOR signaling regulates dMyc protein levels and the activation of dMyc target genes (Teleman et al., 2008Teleman A.A. Hietakangas V. Sayadian A.C. Cohen S.M. Nutritional control of protein biosynthetic capacity by insulin via Myc in Drosophila.Cell Metab. 2008; 7: 21-32Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). In parallel to the molecular machinery that promotes larval tissue growth, a humoral clock times the different developmental stages. In both vertebrates and insects, maturation is triggered by steroid hormones. In Drosophila, larvae progress through a series of molts, the duration of which is determined by a pulse of the steroid hormone 20-hydroxyecdysone (20E, also referred to as ecdysone; reviewed by Thummel, 1996Thummel C.S. Flies on steroids—Drosophila metamorphosis and the mechanisms of steroid hormone action.Trends Genet. 1996; 12: 306-310Abstract Full Text PDF PubMed Scopus (398) Google Scholar). At the end of larval development, a strong induction of ecdysone production promotes growth arrest and the transition to pupal development. Like vertebrate steroids, ecdysone acts through members of the nuclear receptor superfamily that function as ligand-regulated transcription factors. The ecdysone receptor is a heterodimer consisting of two nuclear receptors, EcR and Ultraspiracle (Usp) (reviewed by King-Jones and Thummel, 2005King-Jones K. Thummel C.S. Nuclear receptors—a perspective from Drosophila.Nat. Rev. Genet. 2005; 6: 311-323Crossref PubMed Scopus (402) Google Scholar). Ecdysone rapidly induces early response genes such as those encoding the nuclear receptors E74, E75, and Broad Complex (BR-C), a family of transcription factors. Subsequently, late genes that control the biological responses to each ecdysone pulse are induced, leading to the morphological changes specific to each developmental stage. Many studies suggest that growth and developmental timing are interconnected to establish final body size. Suppression of the prothoracicotropic hormone (PTTH, the hormone that stimulates ecdysone production in the larva) results in a delayed transition to pupal development. As a consequence, animals benefit from a longer larval growth period and eclose as larger flies (McBrayer et al., 2007McBrayer Z. Ono H. Shimell M. Parvy J.P. Beckstead R.B. Warren J.T. Thummel C.S. Dauphin-Villemant C. Gilbert L.I. O'Connor M.B. Prothoracicotropic hormone regulates developmental timing and body size in Drosophila.Dev. Cell. 2007; 13: 857-871Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar). A manipulation of the ras/raf/MAPK signaling pathway in the prothoracic gland (PG, the larval site for ecdysone synthesis) modifies the timing of the ecdysone peak, the timing of the larval/pupal transition, and the size of the adults (Caldwell et al., 2005Caldwell P.E. Walkiewicz M. Stern M. Ras activity in the Drosophila prothoracic gland regulates body size and developmental rate via ecdysone release.Curr. Biol. 2005; 15: 1785-1795Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Drastic changes in PI3-kinase activity in this tissue lead to similar effects (Mirth et al., 2005Mirth C. Truman J.W. Riddiford L.M. The role of the prothoracic gland in determining critical weight for metamorphosis in Drosophila melanogaster.Curr. Biol. 2005; 15: 1796-1807Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). Last, besides its ability to time developmental transitions, the molting hormone ecdysone has also been shown to specifically control the speed at which animals grow, or growth rate. Indeed, changes in circulating ecdysone levels during larval development affect IIS activity in larval tissues and influence final body size (Colombani et al., 2005Colombani J. Bianchini L. Layalle S. Pondeville E. Dauphin-Villemant C. Antoniewski C. Carre C. Noselli S. Leopold P. Antagonistic actions of ecdysone and insulins determine final size in Drosophila.Science. 2005; 310: 667-670Crossref PubMed Scopus (434) Google Scholar). This indicates that IIS and ecdysone signaling pathways carry antagonistic actions that establish the animal growth rate. The physiology and the molecular aspects of the interaction between these two major pathways remain unknown. In the present study, we show that the fat body, the functional homolog of vertebrate liver and adipose tissue, acts as a unique relay tissue for the control of larval growth by circulating ecdysone. The repression of IIS by ecdysone signaling is not required in fat cells to mediate ecdysone-dependent growth inhibition. RNA profiling of dissected fat bodies revealed that EcR signaling represses the Drosophila dMyc gene and its downstream targets. Furthermore, the downregulation of dMyc in fat cells is critical for growth inhibition by ecdysone. We propose a model whereby the rise of ecdysone levels at the end of the juvenile period represses dMyc expression in the fat body. This inhibition restricts ribosome biosynthesis and translation efficiency in fat cells, and induces a general pause in the growth program that precedes entry into metamorphosis. We previously showed that circulating ecdysone impedes the larval growth rate through an antagonistic interaction with IIS (Colombani et al., 2005Colombani J. Bianchini L. Layalle S. Pondeville E. Dauphin-Villemant C. Antoniewski C. Carre C. Noselli S. Leopold P. Antagonistic actions of ecdysone and insulins determine final size in Drosophila.Science. 2005; 310: 667-670Crossref PubMed Scopus (434) Google Scholar). Because IIS is an important regulator of cell growth, we tested the cell-autonomous effects of reducing EcR signaling on cell size. Surprisingly, clonal silencing of EcR and Usp or clonal expression of a dominant-negative form of EcR (EcRF645A) in the fat body led to a reduction of cell size, despite higher levels of IIS (Figure 1A ; see Figures S1A and S1B, available online, for the characterization of the UAS-EcR-RNAi line). The same analysis made in imaginal tissues also showed reduced growth in clones upon EcR loss of function (Figure 1B). More specifically, the cell-doubling time of imaginal cells was strongly increased in clones expressing EcRF645A and moderately affected upon EcR silencing (Figure 1C). These results demonstrate that despite an antagonistic action on IIS, EcR signaling is required for cell growth and cell proliferation in larval and imaginal tissues. Therefore, general growth inhibition exerted by ecdysone does not rely on the cell-autonomous downregulation of IIS by EcR signaling. Larvae with high ecdysone titers due to increased ecdysone synthesis in the PG or following 20E feeding grow slower. Conversely, ubiquitous silencing of EcR during larval development accelerates growth (Colombani et al., 2005Colombani J. Bianchini L. Layalle S. Pondeville E. Dauphin-Villemant C. Antoniewski C. Carre C. Noselli S. Leopold P. Antagonistic actions of ecdysone and insulins determine final size in Drosophila.Science. 2005; 310: 667-670Crossref PubMed Scopus (434) Google Scholar). This effect could be recapitulated by silencing EcR specifically in fat cells, suggesting that the fat body could be the only relay for ecdysone-induced growth inhibition (Colombani et al., 2005Colombani J. Bianchini L. Layalle S. Pondeville E. Dauphin-Villemant C. Antoniewski C. Carre C. Noselli S. Leopold P. Antagonistic actions of ecdysone and insulins determine final size in Drosophila.Science. 2005; 310: 667-670Crossref PubMed Scopus (434) Google Scholar). In order to test this hypothesis, we silenced EcR in various tissues using tissue-specific GAL4 drivers. Three different GAL4 lines highly expressed in this tissue, r4-GAL4 (r4 >), cg-GAL4 (cg >), and ppl-GAL4 (ppl >), induced an increase in pupal volume when crossed with the UAS-EcR-RNAi line (Figure 2A ) without affecting developmental timing (Figure S2A). A similar increase in pupal volume could be observed in cg > UAS-EcRF645A and cg > UAS-USP-RNAi animals (data not shown). All these conditions are pupal lethal. By contrast, no pupal volume increase was observed when EcR was silenced either in the gut, imaginal tissues, muscles, or nervous system (Figure 2A). If the fat body is the unique relay for ecdysone-mediated growth inhibition, we would expect that growth inhibition observed upon 20E feeding could be suppressed by specifically reducing EcR signaling in fat cells. To test this, we fed 20E to larvae where EcR was specifically silenced in the fat body using either ppl >, cg >, or r4 >. Under all conditions, we observed that silencing EcR in the fat body of ppl > EcR-RNAi, r4 > EcR-RNAi, or cg > EcR-RNAi larvae prevented the growth inhibition provoked by 20E feeding (Figures 2B–2D). As a control, specific EcR silencing in the gut (myo1D > EcR-RNAi) did not prevent 20E from generating smaller pupae (Figure 2E). In conclusion, our data indicate that the fat body is the unique relay tissue where EcR signaling nonautonomously regulates the growth rate of the larva. As previously shown, EcR signaling antagonized IIS in the fat body (Colombani et al., 2005Colombani J. Bianchini L. Layalle S. Pondeville E. Dauphin-Villemant C. Antoniewski C. Carre C. Noselli S. Leopold P. Antagonistic actions of ecdysone and insulins determine final size in Drosophila.Science. 2005; 310: 667-670Crossref PubMed Scopus (434) Google Scholar) (Figure S1). This inhibition of IIS in fat cells could be required for the global growth inhibition induced by EcR signaling. To test this, we used conditions where ecdysone biosynthesis is impaired by a reduction of PI3-kinase activity in the PG (P0206 > PI3KDN). In these animals, circulating levels of 20E are reduced and larvae develop into larger pupae and adults (Colombani et al., 2005Colombani J. Bianchini L. Layalle S. Pondeville E. Dauphin-Villemant C. Antoniewski C. Carre C. Noselli S. Leopold P. Antagonistic actions of ecdysone and insulins determine final size in Drosophila.Science. 2005; 310: 667-670Crossref PubMed Scopus (434) Google Scholar). By adding the fat body-specific driver cg-GAL4 to this genetic background, we could carry IIS inhibition in two organs: in the PG, where this induced a reduction of ecdysone production (see Colombani et al., 2005Colombani J. Bianchini L. Layalle S. Pondeville E. Dauphin-Villemant C. Antoniewski C. Carre C. Noselli S. Leopold P. Antagonistic actions of ecdysone and insulins determine final size in Drosophila.Science. 2005; 310: 667-670Crossref PubMed Scopus (434) Google Scholar), and in fat cells, where this counteracted the elevation of PI3K activity (Figures S3A and S3B). This way, we could evaluate whether downregulation of IIS in the fat body could rescue the overgrowth phenotype obtained upon limited synthesis of 20E. P0206 > , cg > PI3KDN animals were not different in size from P0206 > PI3KDN, indicating that reducing IIS in fat cells cannot prevent the increase in pupal size (Figure 3A ). To confirm this result, we silenced both PI3K and EcR specifically in the fat body (cg > EcR-RNAi, > PI3K-RNAi; see Figures S3C and S3D for EcR and dFoxO immunostainings). Again, the overgrowth phenotype observed upon EcR silencing in the fat body was unaffected by reducing IIS in the same place (Figure 3B). We then carried out the converse experiment, where 20E production was increased by silencing PTEN, a negative regulator of IIS, specifically in the PG (P0206 > PTEN-RNAi). As expected, this led to smaller pupae (Figure 3C). Adding the cg > driver in the P0206 > PTEN-RNAi genetic background overactivated IIS in fat body cells as visualized by dFoxO staining (Figures S3E and S3F), but did not interfere with the pupal volume (Figure 3C). Therefore, despite its elevated activity under conditions of reduced EcR signaling, fat-specific IIS is not responsible for the observed systemic growth increase. We then further evaluated the potential role of fat-specific dFoxO in EcR-mediated growth control. Indeed, it was shown previously that clonal inactivation of EcR leads to a relocalization of dFoxO in the cytoplasm of fat cells (Rusten et al., 2004Rusten T.E. Lindmo K. Juhasz G. Sass M. Seglen P.O. Brech A. Stenmark H. Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway.Dev. Cell. 2004; 7: 179-192Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, Colombani et al., 2005Colombani J. Bianchini L. Layalle S. Pondeville E. Dauphin-Villemant C. Antoniewski C. Carre C. Noselli S. Leopold P. Antagonistic actions of ecdysone and insulins determine final size in Drosophila.Science. 2005; 310: 667-670Crossref PubMed Scopus (434) Google Scholar). This could reflect a direct interaction of EcR/Usp with the transcription factor dFoxO, without involving IIS. We therefore tested directly the effect of reducing dFoxO expression on the growth inhibition mediated by 20E feeding. Interestingly, 20E-mediated growth inhibition was still observed when fat dFoxO expression is reduced by RNAi, indicating that, although regulated by EcR activity, fat dFoxO does not contribute to EcR-mediated systemic growth inhibition (Figure 3D). Nevertheless, IIS could still be involved in the growth increase observed upon low fat body EcR expression, acting as a general relay for growth activation. To test this possibility, we observed the levels of peripheral IIS under various conditions of EcR signaling, using dInR transcript levels as a readout (dInR expression is repressed through a feedback loop by IIS; Puig et al., 2003Puig O. Marr M.T. Ruhf M.L. Tjian R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.Genes Dev. 2003; 17: 2006-2020Crossref PubMed Scopus (442) Google Scholar). Silencing EcR in fat cells was accompanied by a general reduction of dInR expression in larval carcasses devoid of fat tissue (Figure 3E). This downregulation was comparable to the one observed upon increased DILP expression (ppl > dilp2F) or general PI3-kinase activation (arm > PI3K; Figure 3E) and was indicative of a global increase of IIS in peripheral larval tissues. Therefore, although not directly involved in the molecular mechanisms taking place in fat cells to control growth in response to EcR signaling, IIS participates in the general growth increase in peripheral tissues. This indicates that EcR signaling in fat cells acts on growth by controlling the production/emission of a humoral message leading to IIS activation in peripheral tissues. Peripheral expression of other growth inducers such as Myc or Cyclin D was unchanged under the same experimental conditions (Figure S4A). In order to identify the downstream targets of EcR signaling in the fat body involved in controlling growth, we compared the transcriptomes of fat bodies dissected from control (cg > W) and cg > EcR-RNAi larvae. Expression of the growth regulator dMyc was significantly upregulated in fat cells upon EcR loss of function (Tables S1 and S2), a result confirmed by qRT-PCR (more than 4-fold induction; Figure 4A ). Accordingly, anti-dMyc immunolabeling detected a marked increase in dMyc protein levels in fat clones expressing the EcR-RNAi construct (Figure 5A ). This induction was specific for fat cells, as dMyc protein levels remained unchanged upon EcR silencing in other larval tissues such as the wing imaginal discs (Figure S5A).Figure 5Fat Body-Targeted EcR Loss of Function Alters dMyc Expression, Nucleolus Size, and Ribosome AbundanceShow full caption(A) EcR silencing increases dMyc expression in the fat body. Clones of fat body cells expressing EcR-RNAi (labeled by nlsGFP, green) (see Figures S1A and S1B) display increased dMyc staining (red).(B) EcR loss of function affects nucleolar size: upon EcR silencing (cells labeled by nlsGFP, green), the nucleoli of fat cells stained with anti-fibrillarin antibodies (red) are markedly bigger.(C) Inhibiting EcR signaling provokes an increase in small subunit ribosome abundance: EcR silencing (cells labeled with nlsGFP, green), reduces RpS6 content (anti-RpS6 antibodies labeled in red).(D) Quantification of the ratio between nucleolus and cell area. n, number of fat body cells. Graph represents mean ± SEM; ∗∗p < 0.01 versus control (nlsGFP overexpression).View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) EcR silencing increases dMyc expression in the fat body. Clones of fat body cells expressing EcR-RNAi (labeled by nlsGFP, green) (see Figures S1A and S1B) display increased dMyc staining (red). (B) EcR loss of function affects nucleolar size: upon EcR silencing (cells labeled by nlsGFP, green), the nucleoli of fat cells stained with anti-fibrillarin antibodies (red) are markedly bigger. (C) Inhibiting EcR signaling provokes an increase in small subunit ribosome abundance: EcR silencing (cells labeled with nlsGFP, green), reduces RpS6 content (anti-RpS6 antibodies labeled in red). (D) Quantification of the ratio between nucleolus and cell area. n, number of fat body cells. Graph represents mean ± SEM; ∗∗p < 0.01 versus control (nlsGFP overexpression). Under the same conditions, the expression of several dMyc target genes (Orian et al., 2003Orian A. van Steensel B. Delrow J. Bussemaker H.J. Li L. Sawado T. Williams E. Loo L.W. Cowley S.M. Yost C. et al.Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network.Genes Dev. 2003; 17: 1101-1114Crossref PubMed Scopus (317) Google Scholar, Pierce et al., 2008Pierce S.B. Yost C. Anderson S.A. Flynn E.M. Delrow J. Eisenman R.N. Drosophila growth and development in the absence of dMyc and dMnt.Dev. Biol. 2008; 315: 303-316Crossref PubMed Scopus (48) Google Scholar) was also induced (dCycD, 2.4-fold; RpI1, 2.7-fold; RpI135, 2.8-fold). dMyc and its target genes were also significantly induced in larvae with reduced circulating levels of ecdysone (P0206 > PI3KDN). Conversely, the same set of genes was moderately repressed upon high ecdysone titer (P0206 > PI3K; Figure 4B). Finally, these manipulations had a limited effect on dMyc expression in dissected body walls (i.e., larval tissues devoid of fat and gut) (Figure S4B) compared to the fat body, confirming that ecdysone regulates dMyc expression specifically in fat cells. These results prompted us to explore the role of fat-specific dMyc in the control of body size. Overexpression of dMyc in the fat body was sufficient to augment pupal volume (cg > dMyc; Figure 4C), whereas silencing of dMyc in fat cells produced smaller animals (Figure 4D). Therefore, adipose dMyc activity regulates organismal growth. Together with our finding that EcR signaling controls adipose dMyc expression, this suggested that dMyc could participate in the control of body size downstream of EcR signaling in the fat body. To test this hypothesis, we combined the silencing of dMyc and EcR in fat cells. Interestingly, cg > dMyc-RNAi and cg > dMyc-RNAi/EcR-RNAi pupae were similarly smaller, indicating that reducing dMyc function fully prevents the pupal overgrowth observed upon EcR silencing (Figure 4D). Silencing of CycD, a known target of dMyc, was not sufficient to prevent the effects of EcR knockdown, suggesting that other dMyc targets are important for this regulation (Figure S5B). This genetic interaction, established in fat cells, indicates that dMyc is acting downstream of EcR signaling to control organism growth. dMyc regulates cell growth in part by controlling the synthesis of ribosomal RNA in the nucleolus and thereby ribosome biogenesis (Grewal et al., 2005Grewal S.S. Li L. Orian A. Eisenman R.N. Edgar B.A. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development.Nat. Cell Biol. 2005; 7: 295-302Crossref PubMed Scopus (283) Google Scholar). Consistent with this, the modification of dMyc levels had a striking effect on the size of fat cell nucleoli (Figures S7A–S7D) (Pierce et al., 2004Pierce S.B. Yost C. Britton J.S. Loo L.W. Flynn E.M. Edgar B.A. Eisenman R.N. dMyc is required for larval growth and endoreplication in Drosophila.Development. 2004; 131: 2317-2327Crossref PubMed Scopus (126) Google Scholar). This was not a consequence of the variation in cell size because the ratio between nucleolar and cellular size was significantly altered (Figure S6E). Silencing EcR in clones of fat cells also induced a marked increase in nucleolus size and the ratio between nucleolus and cell was significantly higher compared to wild-type cells (Figures 5B and 5D). These results suggest that in fat body cells, the regulation of dMyc expression by EcR controls nucleolus size and rRNA synthesis. To evaluate further the role of EcR signaling in ribosome synthesis, we tested whether the abundance of ribosome subunits depended on EcR signaling. For this, we used specific antibodies against the ribosomal protein RpS6, a component of the small ribosome subunit used as a marker of total ribosome number (Wimberly et al., 2000Wimberly B.T. Brodersen D.E. Clemons Jr., W.M. Morgan-Warren R.J. Carter A.P. Vonrhein C. Hartsch T. Ramakrishnan V. Structure of the 30S ribosomal subunit.Nature. 2000; 407: 327-339Crossref PubMed Scopus (1657) Google Scholar). Overexpression of dMyc, used as a control, induced a marked increase of RpS6 in fat cells (Figure S6F). Similarly, RpS6 staining was increased upon EcR silencing (Figure 5C). These experiments indicate that EcR signaling normally reduces ribosome number in fat cells, and suggest that this effect relies on EcR-mediated repression of dMyc levels. Ecdysteroid rises gradually during the third larval instar, with a sharp peak of production just before metamorphosis (Parvy et al., 2005Parvy J.P. Blais C. Bernard F. Warren J.T. Petryk A. Gilbert L.I. O'Connor M.B. Dauphin-Villemant C. A role for βFTZ-F1 in regulating ecdysteroid titers during post-embryonic development in Drosophila melanogaster.Dev. Biol. 2005; 282: 84-94Crossref PubMed Scopus (98) Google Scholar, Warren et al., 2006Warren J.T. Yerushalmi Y. Shimell M.J. O'Connor M.B. Restifo L.L. Gilbert L.I. Discrete pulses of molting hormone, 20-hydroxyecdysone, during late larval development of Drosophila melanogaster: correlations with changes in gene activity.Dev. Dyn. 2006; 235: 315-326Crossref PubMed Scopus (123) Google Scholar). In line with our results showing dMyc repression by EcR signaling, we observed a decrease in dMyc transcript levels throughout the third larval instar (Figure 6B ). During the same period, we observed that the levels of dMyc protein decrease markedly in fat cells (Figure 6A), and this was accompanied by a reduction of the nucleolus/cell ratio and a marked decrease in RpS6 protein levels (Figures 6C–6E). Silencing EcR was sufficient to prevent the decrease in dMyc expression and to provoke an increase in nucleolus size (Figures 6B and 6D). This effect was particularly apparent at 115 hr after egg deposition (AED), when circulating ecdysone reaches its highest level. Therefore, the transition from larval to pupal development is marked by a rise in 20E titers, the downregulation of dMyc expression in the fat body, and, as a consequence, a reduction of ribosome biogenesis and protein translation in fat cells. Together with our data demonstrating the role of adipose dMyc in controlling organismal growth, we propose that this cascade of developmental events is responsible for the reduction of the growth rate that precedes entry into pupal development. In line with this hypothesis, the modification of the protein translation capacity of fat cells has strong effects on systemic growth: the fat-specific knockdown of the translation initiation factor eIF-4E reduces pupal size, whereas knocking down the translation repressor 4E-BP in fat cells increases it (Figure S6G). The growth rate and the duration of juvenile growth are two key parameters that determine the size of the animal at the time of maturation. These two parameters are coupled during the juvenile period to determine organismal size at maturation by mechanisms that are not yet understood. Recent work has established that the two hormonal systems controlling these parameters, ecdysone and insulin/IGF, have antagonistic actions that set up the larval growth rate. The present study demonstrates that the fat body is the unique relay for ecdysone-induced growth inhibition," @default.
• W1994545511 created "2016-06-24" @default.
• W1994545511 creator A5032930792 @default.
• W1994545511 creator A5040300771 @default.
• W1994545511 creator A5045030477 @default.
• W1994545511 date "2010-06-01" @default.
• W1994545511 modified "2023-10-10" @default.
• W1994545511 title "The Steroid Hormone Ecdysone Controls Systemic Growth by Repressing dMyc Function in Drosophila Fat Cells" @default.
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