A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies

Tiu, Gerald C.; Kerr, Craig; Forester, Craig M.; Krishnarao, P. Sivarama; Rosenblatt, Hannah D.; Raj, Nitin; Lantz, Travis C.; Zhulyn, Olena; Bowen, Margot E.; Shokat, Leila; Attardi, Laura D.; Ruggero, Davide; Barna, Maria

doi:10.1016/j.devcel.2021.06.013

Cited by 36 publications

(30 citation statements)

References 78 publications

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“…However, we observed a specificity in translation efficiency depending on the source of the MSC; the humoral-derived MSCs being more susceptible to Rps19 haploinsufficiency in terms of decrease in translation (Figure 6G, left panel). Interestingly, the defect in translation was rescued by the removal of p53, as very recently documented in an Rps6 mutant mouse (Tiu et al, 2021), however this work was only conducted using cells from a single bone type. Altogether, these results suggest that the more severe defects observed in the humeri compared to the femur from Rps19 haploinsufficient animals may be due to specific decreased proliferation and protein synthesis in humoral-derived MSCs.…”

Section: Forelimb-derived Mesenchymal Stem Cells From Rps19 Haploinsufficient Mice Fail Tomentioning

confidence: 84%

Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

Hom

Karnavas

Hartman

et al. 2022

Preprint

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Ribosomopathies are a class of disorders caused by defects in the structure or function of the ribosome and characterized by tissue-specific abnormalities. Diamond Blackfan anemia (DBA) arises from different mutations, predominantly in genes encoding ribosomal proteins (RPs). Apart from the anemia, skeletal defects are among the most common anomalies observed in patients with DBA, but they are virtually restricted to radial ray and other upper limb defects. What leads to these site-specific skeletal defects in DBA remains a mystery. Using a novel mouse model for RP haploinsufficiency, we observed specific, differential defects of the limbs. Using complementary in vitro and in vivo approaches, we demonstrate that reduced WNT signaling and subsequent increased β-catenin degradation in concert with increased expression of p53 contribute to mesenchymal lineage failure. We observed differential defects in the proliferation and differentiation of mesenchymal stem cells (MSCs) from the forelimb versus the hind limbs of the RP haploinsufficient mice that persisted after birth and were partially rescued by allelic reduction of Trp53. These defects are associated with a global decrease in protein translation in RP haploinsufficient MSCs, with the effect more pronounced in cells isolated from the forelimbs. Together these results demonstrate translational differences inherent to the MSC, explaining the site-specific skeletal defects observed in DBA.

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Section: Forelimb-derived Mesenchymal Stem Cells From Rps19 Haploinsufficient Mice Fail Tomentioning

confidence: 84%

Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

Hom

Karnavas

Hartman

et al. 2022

Preprint

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“…Defining the specific developmental stage and cell types that are particularly sensitive to loss of SPATA5 function remains important work for the future. Recent results show that increasing global mRNA translation can partially suppress specific ribosomopathy phenotypes in mice ( Tiu et al, 2021 ). Similar experiments that test whether short-term activation of protein synthesis at specific times during fetal development can improve nervous system development in models of SPATA5 disease should be conducted in the future.…”

Section: Discussionmentioning

confidence: 99%

Labeling of heterochronic ribosomes reveals C1ORF109 and SPATA5 control a late step in human ribosome assembly

Schmitz

Lee

et al. 2022

Cell Reports

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“…The rapid initiation of translation allows erythroid progenitors to immediately respond to environmental cues such as heme and iron availability as well as oxygenation, stimulating erythroid differentiation programs (Moore and von Lindern, 2018; Vatikioti et al, 2019). It is therefore not surprising that multiple translation initiation factors such as eIF4G, eIF2α, EIF4EBP1 have been found to play important roles in erythropoiesis (Alvarez-Dominguez et al, 2017; Paolini et al, 2018; Tiu et al, 2021; Zhang et al, 2019b; Zhang et al, 2018). Moreover, mutations in different ribosomal proteins underlie bone marrow failure syndromes that are associated with anemia.…”

Section: Discussionmentioning

confidence: 99%

Arginine-dependent hypusination of the eukaryotic translation initiation factor (eIF)5A drives erythroid lineage differentiation

González-Menéndez

Phadke

Olive

et al. 2022

Preprint

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Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. We discovered that SLC7A1/CAT1-dependent arginine uptake and its catabolism to spermidine control the erythroid specification of HSPCs via activation of eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on the metabolism of spermidine to hypusine and inhibiting hypusine synthesis abrogates erythropoiesis and diverts EPO-stimulated HSPCs to a myeloid fate. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and induction of mitochondrial function partially rescues erythropoiesis in the absence of hypusine. Within the hypusine network, ribosomal proteins are highly enriched and we identify defective eIF5A hypusination in erythroid pathologies caused by abnormal ribosome biogenesis. Thus, eIF5A-dependent protein synthesis is critical in the branching of erythro-myeloid differentiation and attenuated eIF5A activity characterizes ribosomal protein-linked disorders of ineffective erythropoiesis.

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A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies

Cited by 36 publications

References 78 publications

Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

Labeling of heterochronic ribosomes reveals C1ORF109 and SPATA5 control a late step in human ribosome assembly

Arginine-dependent hypusination of the eukaryotic translation initiation factor (eIF)5A drives erythroid lineage differentiation

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