A Regulatory Response to Ribosomal Protein Mutations Controls Translation, Growth, and Cell Competition

Lee, Young Moo; Kiparaki, Marianthi; Blanco, Jorge Polo; Folgado, Virginia; Ji, Zhejun; Kumar, Amit; Rimesso, Gerard; Baker, Nicholas E.

doi:10.1016/j.devcel.2018.07.003

Cited by 89 publications

(185 citation statements)

References 79 publications

(103 reference statements)

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“…Kale et al recently established that RpS12 is required to trigger Minute cell competition, and that the relative levels of RpS12 define cell competitiveness. Moreover, recent data from Baker's group indicates that RpS12 is required for xrp1 expression in Minute clones (Lee et al, 2018). We bring here the remarkable finding that removing RpS12, while inducing autonomous growth inhibition by itself, rescues the Xrp1/Dilp8 non-autonomous response in the context of already Rp-RNAi discs.…”

Section: Rps12 As a Sensor For Ribosomal Protein Functionmentioning

confidence: 52%

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

et al. 2019

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How organs scale with other body parts is not mechanistically understood. We have addressed this question using the Drosophila imaginal disc model. When growth of one disc domain is perturbed, other parts of the disc and other discs slow down their growth, maintaining proper inter-disc and intra-disc proportions. We show here that the relaxin-like Dilp8 is required for this inter-organ coordination. Our work also reveals that the stress-response transcription factor Xrp1 plays a key role upstream of dilp8 in linking organ growth status with non-autonomous/systemic growth response. In addition, we show that the small ribosomal subunit protein RpS12 is required to trigger Xrp1-dependent non-autonomous response. Our work demonstrates that RpS12, Xrp1 and Dilp8 constitute an independent regulatory module that ensures intra-and inter-organ growth coordination during development.

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Section: Rps12 As a Sensor For Ribosomal Protein Functionmentioning

confidence: 52%

“…Two recent studies report that Xrp1 is required in Minute clones to induce cell competition by surrounding wild-type cells (Baillon et al, 2018;Lee et al, 2018). This work reveals that Xrp1 mediates most of the changes in gene expression and translation inhibition observed in Minute cells.…”

Section: Xrp1 Cell Competition and Size Adjustmentmentioning

confidence: 70%

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

et al. 2019

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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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“…This was recently demonstrated experimentally by the O-propargyl-puromycin (OPP) assay in Drosophila imaginal disc (Lee et al, 2018). Intriguingly, the reduction of protein synthesis in M/+ cells is mediated by upregulation of the bZip-domain protein Xrp1 (Lee et al, 2018). On the other hand, overexpression of Myc upregulates protein synthesis in both mammalian cells (Iritani & Eisenman, 1999) and Drosophila (Rina Nagata (RN) and Tatsushi Igaki (TI), unpublished data), while reduction of Myc leads to a decrease in protein synthesis in Drosophila imaginal disc (Pierce et al, 2008).…”

Section: S Elec Ti On Of Fit Ter Cell S: Minute or Myc-induced Cellmentioning

confidence: 93%

“…Minute flies have loss-of-function mutations in the ribosomal protein genes (Lambertsson, 1998), and thus it has been thought that global protein synthesis is reduced in M/+ cells. This was recently demonstrated experimentally by the O-propargyl-puromycin (OPP) assay in Drosophila imaginal disc (Lee et al, 2018). Intriguingly, the reduction of protein synthesis in M/+ cells is mediated by upregulation of the bZip-domain protein Xrp1 (Lee et al, 2018).…”

Section: S Elec Ti On Of Fit Ter Cell S: Minute or Myc-induced Cellmentioning

confidence: 94%

Cell competition: Emerging mechanisms to eliminate neighbors

Nagata

Igaki

2018

Dev Growth Differ

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Cell competition is a context‐dependent cell elimination through short‐range cell–cell interaction, in which cells with higher fitness eliminate neighboring less‐fit or oncogenic cells within the growing tissue. Cell competition can be triggered by many different factors such as heterozygous mutations in the ribosomal protein genes (which are called “Minute” mutations), elevated Myc, Yorkie/YAP, Wg/Wnt, JAK‐STAT, Ras, or Src activity, and loss of Mahjong/VprBP, endocytic pathway components, or apicobasal cell polarity. Studies on the mechanisms and roles of cell competition have suggested that cell competition can be divided into two types: selection of fitter cells or elimination of oncogenic cells. The former type of cell competition includes Minute or Myc‐induced cell competition that is considered to be dependent on the relative level of protein synthesis. The later type of cell competition includes tumor‐suppressive cell competition triggered by loss of cell polarity genes such as scribble (scrib) or discs large (dlg). Genetic studies in Drosophila during the past decade have provided significant progress in understanding the mechanisms of these phenomena. At the same time, these studies have now raised new questions; how do different mechanisms contribute or cooperate to drive cell competition, do common mechanisms exist in different types of cell competition, and what are the physiological roles of these cell competition phenomena?

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A Regulatory Response to Ribosomal Protein Mutations Controls Translation, Growth, and Cell Competition

Cited by 89 publications

References 79 publications

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

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

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

Cell competition: Emerging mechanisms to eliminate neighbors

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