Drosophila Ribosomal Protein Mutants Control Tissue Growth Non-Autonomously via Effects on the Prothoracic Gland and Ecdysone

Lin, Jane I.; Mitchell, Naomi C; Kalcina, Marina; Tchoubrieva, Elissaveta B; Stewart, Michael; Marygold, Steven J; Walker, Cherryl D.; Thomas, George; Leevers, Sally J.; Pearson, Richard B.; Quinn, Leonie M.; Hannan, Ross D.

doi:10.1371/journal.pgen.1002408

Cited by 33 publications

(30 citation statements)

References 66 publications

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“…It is known that mutations in ribosomal proteins can provoke growth defects in Drosophila, such as those observed after Sud1 knockdown (26,27). Consistent with this, in refs.…”

Section: Sudestada1supporting

confidence: 68%

Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth

Katz

Acevedo

Loenarz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Genome sequences predict the presence of many 2-oxoglutarate (2OG)-dependent oxygenases of unknown biochemical and biological functions in Drosophila. Ribosomal protein hydroxylation is emerging as an important 2OG oxygenase catalyzed pathway, but its biological functions are unclear. We report investigations on the function of Sudestada1 (Sud1), a Drosophila ribosomal oxygenase. As with its human and yeast homologs, OGFOD1 and Tpa1p, respectively, we identified Sud1 to catalyze prolyl-hydroxylation of the small ribosomal subunit protein RPS23. Like OGFOD1, Sud1 catalyzes a single prolyl-hydroxylation of RPS23 in contrast to yeast Tpa1p, where Pro-64 dihydroxylation is observed. RNAi-mediated Sud1 knockdown hinders normal growth in different Drosophila tissues. Growth impairment originates from both reduction of cell size and diminution of the number of cells and correlates with impaired translation efficiency and activation of the unfolded protein response in the endoplasmic reticulum. This is accompanied by phosphorylation of eIF2α and concomitant formation of stress granules, as well as promotion of autophagy and apoptosis. These observations, together with those on enzyme homologs described in the companion articles, reveal conserved biochemical and biological roles for a widely distributed ribosomal oxygenase.fruit fly | ribosome | dioxygenase | proline | tranlational stress I ron [Fe(II)]-and 2-oxoglutarate (2OG)-dependent oxygenases are a superfamily with diverse biochemical and biological functions. During 2OG oxygenase catalysis, substrate oxidation is coupled to decarboxylation of 2OG, yielding succinate and carbon dioxide (1, 2). Structural studies reveal that the catalytic domain of 2OG oxygenases contains a conserved double-stranded β-helix (DSBH) fold presenting an HXD. . .H facial triad motif that coordinates an Fe(II) cofactor (3, 4). These and other structural features have been used to predict the existence of multiple uncharacterized 2OG oxygenases. In contrast to microorganisms and plants where 2OG oxygenases catalyze a wide variety of oxidative reactions, in animals their biochemical activities appear limited to hydroxylations or demethylations via hydroxylation (1,5,6). Despite progress in making biochemical assignments, the physiological roles of most 2OG oxygenases predicted by bioinformatic analysis of animal genomes are unknown. For instance, we have identified ∼50 putative 2OG oxygenases in the Drosophila genome, but only a few are characterized (7,8).The function of Fatiga, the single Drosophila homolog of human hypoxia inducible transcription factor (HIF) prolyl-4-hydroxylases (PHDs), has been well studied in the context of oxygen sensing (9). HIF prolyl-hydroxylation plays a central role in the animal hypoxic response via hydroxylation of HIF, a posttranslational modification that signals for HIF-α degradation in a physiologically relevant oxygen-dependent manner (10, 11). Given the tractability of these enzymes as targets for pharmacological modulation by 2OG analogs and related co...

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“…It is known that mutations in ribosomal proteins can provoke growth defects in Drosophila, such as those observed after Sud1 knockdown (26,27). Consistent with this, in refs.…”

Section: Sudestada1supporting

confidence: 68%

Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth

Katz

Acevedo

Loenarz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, systemic changes in insulin/IGF‐signaling do not affect critical size or (substantially) the duration of the TGP but reduce growth rate during the TGP, thereby reducing final body and organ size . In contrast, perturbations in ribosomal function also slow growth rate but delay the synthesis of ecdysone, largely eliminating any effect on final body and organ size …”

Section: Aspects Of Size Controlmentioning

confidence: 99%

Size control: the developmental physiology of body and organ size regulation

Gokhale

Shingleton

2015

WIREs Developmental Biology

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The developmental regulation of final body and organ size is fundamental to generating a functional and correctly proportioned adult. Research over the last two decades has identified a long list of genes and signaling pathways that, when perturbed, influence final body size. However, body and organ size are ultimately a characteristic of the whole organism, and how these myriad genes and pathways function within a physiological context to control size remains largely unknown. In this review, we first describe the major size-regulatory signaling pathways: the Insulin/IGF-, RAS/RAF/MAPK-, TOR-, Hippo-, and JNK-signaling pathways. We then explore what is known of how these pathways regulate five major aspects of size regulation: growth rate, growth duration, target size, negative growth and growth coordination. While this review is by no means exhaustive, our goal is to provide a conceptual framework for integrating the mechanisms of size control at a molecular-genetic level with the mechanisms of size control at a physiological level.

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“…Ecdysone pulses therefore control developmental timing and growth of a range of larval tissues [28-30], but how does ecdysone achieve these changes in cell growth and cell cycle progression? In particular, how does ecdysone connect with the major developmental signaling pathways that regulate cell cycle patterning in Drosophila imaginal tissues?…”

Section: Introductionmentioning

confidence: 99%

The Ecdysone receptor constrains wingless expression to pattern cell cycle across the Drosophilawing margin in a cyclin B-dependent manner

et al. 2013

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BackgroundEcdysone triggers transcriptional changes via the ecdysone receptor (EcR) to coordinate developmental programs of apoptosis, cell cycle and differentiation. Data suggests EcR affects cell cycle gene expression indirectly and here we identify Wingless as an intermediary factor linking EcR to cell cycle.ResultsWe demonstrate EcR patterns cell cycle across the presumptive Drosophila wing margin by constraining wg transcription to modulate CycB expression, but not the previously identified Wg-targets dMyc or Stg. Furthermore co-knockdown of Wg restores CycB patterning in EcR knockdown clones. Wg is not a direct target of EcR, rather we demonstrate that repression of Wg by EcR is likely mediated by direct interaction between the EcR-responsive zinc finger transcription factor Crol and the wg promoter.ConclusionsThus we elucidate a critical mechanism potentially connecting ecdysone with patterning signals to ensure correct timing of cell cycle exit and differentiation during margin wing development.

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Drosophila Ribosomal Protein Mutants Control Tissue Growth Non-Autonomously via Effects on the Prothoracic Gland and Ecdysone

Cited by 33 publications

References 66 publications

Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth

Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth

Size control: the developmental physiology of body and organ size regulation

The Ecdysone receptor constrains wingless expression to pattern cell cycle across the Drosophilawing margin in a cyclin B-dependent manner

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