Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function

Jones, Natalie Carmaline; Lynn, Megan L.; Gaudenz, Karin; Sakai, Daisuke; Aoto, Kazushi; Rey, Jean-Phillipe; Glynn, Earl; Ellington, Lacey R.; Du, Can; Dixon, Jill; Dixon, Michael J.; Trainor, Paul A.

doi:10.1038/nm1725

Cited by 396 publications

(521 citation statements)

References 31 publications

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“…They also complement a recent analysis of pancreas-specific deletion of murine Sbds (Tourlakis et al, 2012), and implicate defective proliferation of ptf1a-expressing pancreatic progenitor cells as a basis for the observed pancreatic phenotype. The zebrafish Sbds knockdown phenotype was not rescued by loss of p53, suggesting that, in contrast to Treacher Collins syndrome and 5q-syndrome (Jones et al, 2008;Barlow et al, 2010), SDS is a largely p53-independent ribosomopathy. Furthermore, by unbiased screening of genes exhibiting altered expression following Sbds knockdown, we have identified a previously unappreciated requirement for additional genes related to ribosome assembly in early pancreas development.…”

Section: Discussionmentioning

confidence: 94%

“…When normal ribosome biogenesis is disrupted, a resulting p53 response is commonly accepted to play a role in the associated disease phenotypes (Lohrum et al, 2003;Dai and Lu, 2004;Jin et al, 2004;Danilova et al, 2008;Jones et al, 2008;Barlow et al, 2010;Duan et al, 2011;Sasaki et al, 2011). To determine whether SDS disease phenotypes are similarly p53 dependent, we evaluated the influence of p53 inactivation on the organogenesis defects induced by Sbds ATG MO injection, using both MO-mediated p53 knockdown and available p53 mutant alleles.…”

Section: Loss Of P53 Does Not Rescue the Sbds Organogenesis Phenotypesmentioning

confidence: 99%

“…Models of DBA in mice and zebrafish have suggested a role for p53 (Tp53/Trp53) in mediating the disease phenotype (Danilova et al, 2008;McGowan et al, 2008;Uechi et al, 2008). Mice with mutations in Rps19 are phenotypically rescued by homozygous loss of p53 (McGowan et al, 2008), as are other mouse models of human ribosomopathies, including 5q-syndrome and Treacher Collins syndrome (Jones et al, 2008;Barlow et al, 2010). Thus, it is generally appreciated that ribosomopathies mediate their phenotype through p53-dependent mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 94%

Section: Loss Of P53 Does Not Rescue the Sbds Organogenesis Phenotypesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…71 Interestingly, a study by Jones et al showed that chemical and genetic inhibition of p53 activity in these mice can prevent the craniofacial abnormalities. 72 This is of special note, and the link between p53 and ribosomopathies is discussed in greater detail later in this review.…”

Section: Treacher Collins Syndromementioning

confidence: 96%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

698

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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“…However, mice with a point mutation in rps19 do have a hematopoietic defect that is rescued by p53 knockdown[11]. p53 inactivation also rescues craniofacial abnormalities in mouse models of Treacher Collins Syndrome, where mutations affect ribosome biogenesis[12]. In a mouse model of conditional rps6 knockdown, p53 is activated[13].…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation

Taylor

Humphries

White

et al. 2012

Experimental Hematology

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Disruption of ribosomal proteins is associated with hematopoietic phenotypes in cell culture and animal models. Mutations in ribosomal proteins are seen in patients with Diamond Blackfan anemia (DBA), a rare congenital disease characterized by red cell aplasia and distinctive craniofacial anomalies. A zebrafish screen uncovered decreased hematopoietic stem cells (HSCs) in embryos with mutations in ribosomal protein rps29. Here, we determined that rps29-/- embryos also have red blood cell defects and increased apoptosis in the head. As the p53 pathway has been shown to play a role in other ribosomal protein mutants, we studied the genetic relationship of rps29 and p53. Transcriptional profiling revealed that genes up-regulated in the rps29 mutant are enriched for genes up-regulated by p53 after irradiation. p53 mutation near completely rescues the rps29 morphological and hematopoietic phenotypes, demonstrating that p53 mediates the effects of rps29 knockdown. We also identified neuronal gene orthopedia protein a (otpa) as one whose expression correlates with rps29 expression, suggesting that levels of expression of some genes are dependent on rps29 levels. Together, our studies demonstrate a role of p53 in mediating the cellular defects associated with rps29 and establish a role for rps29 and p53 in HSCs and red blood cell development.

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Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function

Cited by 396 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

Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation

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