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

Elayne Provost, Karen A. Wehner, Xiangang Zhong, Foram Ashar, Elizabeth Nguyen, Rachel Green, Michael J. Parsons, Steven D. Leach

Research output: Contribution to journalArticle

Abstract

Mutations 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.

Original languageEnglish (US)
Pages (from-to)3232-3241
Number of pages10
JournalDevelopment
Volume139
Issue number17
DOIs
StatePublished - Sep 1 2012

Fingerprint

Essential Genes
p53 Genes
Zebrafish
Pancreas
Ribosomes
Phenotype
Stem Cells
Genes
Exocrine Pancreatic Insufficiency
Mutation
Organogenesis
Neutropenia
Embryonic Structures
ribosomal protein L3

Keywords

  • p53 (tp53)
  • Pescadillo
  • Ribosome
  • rpl3
  • Sbds
  • Shwachman-diamond syndrome
  • Zebrafish

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

Cite this

Provost, E., Wehner, K. A., Zhong, X., Ashar, F., Nguyen, E., Green, R., ... Leach, S. D. (2012). Ribosomal biogenesis genes play an essential and p53- independent role in zebrafish pancreas development. Development, 139(17), 3232-3241. https://doi.org/10.1242/dev.077107

Ribosomal biogenesis genes play an essential and p53- independent role in zebrafish pancreas development. / Provost, Elayne; Wehner, Karen A.; Zhong, Xiangang; Ashar, Foram; Nguyen, Elizabeth; Green, Rachel; Parsons, Michael J.; Leach, Steven D.

In: Development, Vol. 139, No. 17, 01.09.2012, p. 3232-3241.

Research output: Contribution to journalArticle

Provost, E, Wehner, KA, Zhong, X, Ashar, F, Nguyen, E, Green, R, Parsons, MJ & Leach, SD 2012, 'Ribosomal biogenesis genes play an essential and p53- independent role in zebrafish pancreas development', Development, vol. 139, no. 17, pp. 3232-3241. https://doi.org/10.1242/dev.077107
Provost, Elayne ; Wehner, Karen A. ; Zhong, Xiangang ; Ashar, Foram ; Nguyen, Elizabeth ; Green, Rachel ; Parsons, Michael J. ; Leach, Steven D. / Ribosomal biogenesis genes play an essential and p53- independent role in zebrafish pancreas development. In: Development. 2012 ; Vol. 139, No. 17. pp. 3232-3241.
@article{0bf7afdd50344ff384b137cef6edc44b,
title = "Ribosomal biogenesis genes play an essential and p53- independent role in zebrafish pancreas development",
abstract = "Mutations 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.",
keywords = "p53 (tp53), Pescadillo, Ribosome, rpl3, Sbds, Shwachman-diamond syndrome, Zebrafish",
author = "Elayne Provost and Wehner, {Karen A.} and Xiangang Zhong and Foram Ashar and Elizabeth Nguyen and Rachel Green and Parsons, {Michael J.} and Leach, {Steven D.}",
year = "2012",
month = "9",
day = "1",
doi = "10.1242/dev.077107",
language = "English (US)",
volume = "139",
pages = "3232--3241",
journal = "Development (Cambridge)",
issn = "0950-1991",
publisher = "Company of Biologists Ltd",
number = "17",

}

TY - JOUR

T1 - Ribosomal biogenesis genes play an essential and p53- independent role in zebrafish pancreas development

AU - Provost, Elayne

AU - Wehner, Karen A.

AU - Zhong, Xiangang

AU - Ashar, Foram

AU - Nguyen, Elizabeth

AU - Green, Rachel

AU - Parsons, Michael J.

AU - Leach, Steven D.

PY - 2012/9/1

Y1 - 2012/9/1

N2 - Mutations 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.

AB - Mutations 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.

KW - p53 (tp53)

KW - Pescadillo

KW - Ribosome

KW - rpl3

KW - Sbds

KW - Shwachman-diamond syndrome

KW - Zebrafish

UR - http://www.scopus.com/inward/record.url?scp=84864858368&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864858368&partnerID=8YFLogxK

U2 - 10.1242/dev.077107

DO - 10.1242/dev.077107

M3 - Article

C2 - 22872088

AN - SCOPUS:84864858368

VL - 139

SP - 3232

EP - 3241

JO - Development (Cambridge)

JF - Development (Cambridge)

SN - 0950-1991

IS - 17

ER -