SBDS Expression and Localization at the Mitotic Spindle in Human Myeloid Progenitors

Orelio, Claudia; Verkuijlen, Paul; Geissler, Judy; Berg, Timo K. van den; Kuijpers, Taco W.

doi:10.1371/journal.pone.0007084

Cited by 41 publications

(35 citation statements)

References 31 publications

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“…To further explore the mechanism underlying the hypoplastic pancreas phenotype of Sbds ATG MO-injected embryos, we analyzed phospho-histone H3 (pHH3) labeling of ptf1a-expressing pancreatic progenitor cells at 48 hpf. Similar to previous reports suggesting that Sbds might influence cellular proliferation (Zhang et al, 2006;Orelio et al, 2009), we observed a decrease in the number of pHH3-positive mitotic cells within the ptf1a:eGFP-defined pancreatic progenitor population at 48 hpf ( Fig. 2E), with several sbds morphant embryos showing a complete absence of pHH3 labeling within the ptf1a:eGFP expression domain.…”

Section: Loss Of Sbds Results In Defective Proliferation Of Pancreatisupporting

confidence: 91%

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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SUMMARYMutations in the human Shwachman-Bodian-Diamond syndrome (SBDS) gene cause defective ribosome assembly and are associated with exocrine pancreatic insufficiency, chronic neutropenia and skeletal defects. However, the mechanism underlying these phenotypes remains unclear. Here we show that knockdown of the zebrafish sbds ortholog fully recapitulates the spectrum of developmental abnormalities observed in the human syndrome, and further implicate impaired proliferation of ptf1a-expressing pancreatic progenitor cells as the basis for the observed pancreatic phenotype. It is thought that diseases of ribosome assembly share a p53-dependent mechanism. However, loss of p53 did not rescue the developmental defects associated with loss of zebrafish sbds. To clarify the molecular mechanisms underlying the observed organogenesis defects, we performed transcriptional profiling to identify candidate downstream mediators of the sbds phenotype. Among transcripts displaying differential expression, functional group analysis revealed marked enrichment of genes related to ribosome biogenesis, rRNA processing and translational initiation. Among these, ribosomal protein L3 (rpl3) and pescadillo (pes) were selected for additional analysis. Similar to knockdown of sbds, knockdown or mutation of either rpl3 or pes resulted in impaired expansion of pancreatic progenitor cells. The pancreatic phenotypes observed in rpl3-and pes-deficient embryos were also independent of p53. Together, these data suggest novel p53-independent roles for ribosomal biogenesis genes in zebrafish pancreas development.

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Section: Loss Of Sbds Results In Defective Proliferation Of Pancreatisupporting

confidence: 91%

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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“…44 Although these findings provide evidence for a role of SBDS in ribosome biogenesis, SBDS is a multifunctional protein, and nonribosomal activities may play a dominant role in the clinical phenotype. In particular, SBDS has been shown to have a role in stabilizing the mitotic spindle, 46,47 which might indicate a role for SBDS in proliferation and/or chromosome segregation, thereby contributing to chromosomal instability and some component of bone marrow failure.…”

Section: Q؊ Syndromementioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

691

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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“…72 Observations of in vitro assays for abnormalities of marrow stroma from SDS patients have varied. 73,74 A variety of cellular phenotypes has been observed in SDS, including mitotic spindle destabilization, 75,76 Fas ligand-induced apoptosis, 77 heightened cellular stress responses 78 and Rac2-mediated monocyte migration, 79 decreased mitochondrial membrane potential and oxygen consumption, and increased the production of reactive oxygen species. 80,81 SBDS promotes the release of EIF6 from the pre-60S ribosome, which is required for the formation of a mature 80S functional ribosome [82][83][84] (Figure 2).…”

Section: Shwachman-diamond Syndrome: Molecular Pathophysiologymentioning

confidence: 99%

Marrow failure: a window into ribosome biology

Ruggero

Shimamura

2014

Blood

101

107

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Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita are inherited syndromes characterized by marrow failure, congenital anomalies, and cancer predisposition. Genetic and molecular studies have uncovered distinct abnormalities in ribosome biogenesis underlying each of these 3 disorders. How defects in ribosomes, the essential organelles required for protein biosynthesis in all cells, cause tissue-specific abnormalities in human disease remains a question of fundamental scientific and medical importance. Here we review the overlapping and distinct clinical features of these 3 syndromes and discuss current knowledge regarding the ribosomal pathways disrupted in each of these disorders. We also explore the increasing complexity of ribosome biology and how this informs our understanding of developmental biology and human disease.

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SBDS Expression and Localization at the Mitotic Spindle in Human Myeloid Progenitors

Cited by 41 publications

References 31 publications

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

Ribosomopathies: human disorders of ribosome dysfunction

Marrow failure: a window into ribosome biology

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