Inter-Organ Growth Coordination Is Mediated by the Xrp1-Dilp8 Axis in Drosophila

Boulan, Laura; Andersen, Ditte S.; Colombani, Julien; Boone, Émilie; Léopold, Pierre

doi:10.1016/j.devcel.2019.03.016

Cited by 65 publications

(93 citation statements)

References 37 publications

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“…Here we provided evidences that JNK coordinates intra-organ growth in a Jun/Fos-dependent manner through a mechanism involving expression of Dilp8 and generation of ROS, two different signaling events that independently regulate tissue size and cell number. Dilp8 has been recently identified as a signaling molecule produced by damaged imaginal discs able to delay metamorphosis and systemically reduce growth [39,40,57]. In developing wing discs, we have showed that Dilp8 expression in slow growing cell populations contribute to size reduction of adjacent wild-type territories, thereby contributing to organ proportion maintenance.…”

Section: Discussionmentioning

confidence: 74%

“…Interestingly, when activation of JNK pathway was reduced, either by using Dilp8 is required to coordinate intra-organ growth downstream of Eiger/JNK signaling Recently, Drosophila insulin-like peptide 8 (Dilp8) has been identified as a signaling molecule produced by imaginal discs in response to tissue damage [39,40]. Dilp8 production by slow growing or damaged tissues results in activation of neuronal receptor Lgr3 which in turn downregulates ecdysone synthesis therefore delaying metamorphosis and systemically reducing growth [39][40][41][42][43]. Interestingly, we observed a strong induction of dilp8 transcript levels upon RA CS or dmyc RNAi expression ( Figure 5A, Figure S1 and Table S1).…”

Section: Eiger-induced Jnk Signaling Is Required For Non-cell-autonommentioning

confidence: 99%

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Eiger/TNFα-mediated Dilp8 and ROS production coordinate intra-organ growth inDrosophila

Sánchez

Mesquita

Ingaramo

et al. 2019

Preprint

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HIGHLIGHTS ✓ Dmp53-dependent Eiger expression is required to coordinate intra-organ growth ✓ Eiger acts through its receptor Grindelwald and JNK signaling to reduce growth and proliferation rates in a non-cell-autonomous manner ✓ Eiger/JNK-dependent Dilp8 expression coordinates intra-organ growth but not proliferation ✓ Eiger/JNK activation triggers ROS production ✓ ROS act non-cell-autonomously to regulate proliferation of adjacent epithelial cells. ABSTRACTCoordinated intra-and inter-organ growth is essential during animal development to generate individuals of proper size and shape. The Drosophila wing has been a valuable model system to reveal the existence of a stress response mechanism mediated by Drosophila p53 (Dmp53) and involved in the coordination of tissue growth between adjacent cell populations upon targeted reduction of growth rates. Here we present evidence that a two-step molecular mechanism is being used by Dmp53 to reduce in a non-autonomous manner growth and proliferation in adjacent cell populations. First, Dmp53-mediated transcriptional induction of Drosophila TNFα ligand Eiger leads to cell autonomous activation of JNK. Second, two different signaling events downstream of the Eiger/JNK axis are induced in the growth depleted territory in order to independently regulate tissue size and cell number in adjacent cell populations. Whereas expression of the systemic hormone dILP8 coordinates intra-organ growth and final tissue size, induction of Reactive Oxygen Species downstream of Eiger/JNK and, as a consequence of apoptosis induction, acts non-cellautonomously to regulate proliferation rates of adjacent epithelial cells. Our results unravel how local and systemic signals can act concertedly to coordinate growth and proliferation within an organ in order to generate well-proportioned organs and functionally integrated adults.

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Section: Discussionmentioning

confidence: 74%

Section: Eiger-induced Jnk Signaling Is Required For Non-cell-autonommentioning

confidence: 99%

Eiger/TNFα-mediated Dilp8 and ROS production coordinate intra-organ growth inDrosophila

Sánchez

Mesquita

Ingaramo

et al. 2019

Preprint

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“…Finally, we show that similarly to what was previously described for Ras signaling (Atkins et al, 2016), the cooperation between Notch signaling and polarity loss is controlled by a “tumor transcriptional network” centered around the AP-1/Stat/Yki transcription factors, and including the critical bZIP factors Pdp1 and CEPBG (CG6272/Irbp18). But our analysis uncovered a previously unreported role for the cell competition regulator, and Irbp18 binding partner Xrp1 (Baillon et al, 2018; Blanco et al, 2020; Boulan et al, 2019; Ji et al, 2019), raising the interesting prospect that neoplastic growth could be mediated at least in part, by co-opting cell competition.…”

Section: Discussionmentioning

confidence: 80%

“…This would align with the NS specific GO categories “cellular response to gamma radiation” (GO:0071480), and “DNA damage checkpoints” (GO:0031571/0007095). Indeed, Xrp1 has recently been linked to cell competition and shown to control the expression of a subset of genes activated in response to Ribosomal protein haplo-insufficiency including Ets21C , upd3 , or ilp8 in developing wing discs (Baillon et al, 2018; Boulan et al, 2019; Ji et al, 2019). Strikingly, we observed a very strong overlap between the Xrp1 transcriptional program (Supplemental Table S16) and the genes activated in NS (60 out of the 171 Xrp1 positively regulated genes are also upregulated in NS; hypergeometric test, p=4.71 10e-21), while a much more modest overlap could be observed with N or S (overlap of 17 and 33 with p values of 1.12 10e-3 and 1.56 10e-8 respectively).…”

Section: Resultsmentioning

confidence: 99%

Mechanisms underlying the cooperation between loss of epithelial polarity and Notch signaling during neoplastic growth in Drosophila

Logeay¹,

Géminard²,

Lassus³

et al. 2020

Preprint

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SUMMARYAggressive neoplastic growth can be initiated by a limited number of genetic alterations, such as the well-established cooperation between loss of cell architecture and hyperactive signaling pathways. However, our understanding of how these different alterations interact and influence each other remains very incomplete. Using Drosophila paradigms of imaginal wing disc epithelial growth, we have monitored the changes in Notch pathway activity according to the polarity status of cells and show that epithelial polarity changes directly impact the transcriptional output of the Notch pathway. Importantly, we show that this Notch pathway redirection is not mediated by a redeployment of Su(H), the Notch dedicated transcription factor, but relies on the cooperation with a combination of oncogenic transcription factors. Our work highlights in particular the role of the stress response CEBPG homologue CG6272/Irbp18 and of its partner Xrp1 suggesting that parts of the cellular competition program might promote neoplastic growth.

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“…Mallik et al recently reported that neuronal dysfunction in caz loss-of-function mutants is mediated by increased expression of Xrp1 [10], a DNA-binding protein involved in protection against genotoxic stress [17], DNA damage repair [18], cell competition [19,20] and intra-and inter-organ growth coordination [21]. Increased Xrp1 expression in caz mutant central nervous system led to gene expression dysregulation and neuronal dysfunction [10].…”

Section: Discussionmentioning

confidence: 99%

TheDrosophila FUSorthologcabezapromotes adult founder myoblast selection by Xrp1-dependent regulation of FGF signaling

Catinozzi

Mallik

Frickenhaus

et al. 2020

Preprint

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AbstractThe number of adult myofibers in Drosophila is determined by the number of founder myoblasts selected from a myoblast pool, a process governed by fibroblast growth factor (FGF) signaling. Here, we show that loss of cabeza (caz) function results in a reduced number of adult founder myoblasts, leading to a reduced number and misorientation of adult dorsal abdominal muscles. Genetic experiments revealed that loss of caz function in both adult myoblasts and neurons contributes to caz mutant muscle phenotypes. Selective overexpression of the FGF receptor Htl or the FGF receptor-specific signaling molecule Stumps in adult myoblasts partially rescued caz mutant muscle phenotypes, and Stumps levels were reduced in caz mutant founder myoblasts, indicating FGF pathway deregulation. In both adult myoblasts and neurons, caz mutant muscle phenotypes were mediated by increased expression levels of Xrp1, a DNA-binding protein involved in gene expression regulation. Xrp1-induced phenotypes were dependent on the DNA-binding capacity of its AT-hook motif, and increased Xrp1 levels in founder myoblasts reduced Stumps expression. Thus, control of Xrp1 expression by Caz is required for regulation of Stumps expression in founder myoblasts, resulting in correct founder myoblast selection.Author SummarySkeletal muscles mediate movement, and therefore, proper structure and function of skeletal muscles is required for respiration, locomotion, and posture. Adult muscles arise from fusion of muscle precursor cells during development. In the fruit fly Drosophila melanogaster, muscle precursor cells come in two flavors: founder cells and fusion-competent cells. The number of founder cells selected during development corresponds to the number of adult muscles formed. Here, we report that inactivation of the Drosophila caz gene results in muscle developmental defects. Loss of caz function in both muscle precursor cells and the nerve cells that innervate muscles contributes to the muscle developmental defect. At the molecular level, loss of caz function leads to increased levels of Xrp1. Xrp1 regulates the expression of many other genes, including genes that produce components of the FGF signaling pathway, which is known to be involved in founder cell selection. In all, we uncovered a novel molecular mechanism that regulates founder cell selection during muscle development.

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Inter-Organ Growth Coordination Is Mediated by the Xrp1-Dilp8 Axis in Drosophila

Cited by 65 publications

References 37 publications

Eiger/TNFα-mediated Dilp8 and ROS production coordinate intra-organ growth inDrosophila

Eiger/TNFα-mediated Dilp8 and ROS production coordinate intra-organ growth inDrosophila

Mechanisms underlying the cooperation between loss of epithelial polarity and Notch signaling during neoplastic growth in Drosophila

TheDrosophila FUSorthologcabezapromotes adult founder myoblast selection by Xrp1-dependent regulation of FGF signaling

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