Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation.
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, a rare congenital disease characterized by red cell aplasia and distinctive craniofacial anomalies. A zebrafish screen uncovered decreased hematopoietic stem cells 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 upregulated in the rps29 mutant are enriched for genes upregulated 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 hematopoietic stem cells and red blood cell development.
Pubmed ID: 22120640 RIS Download
Anemia, Diamond-Blackfan | Animals | Apoptosis | Bone and Bones | Cell Cycle | DNA Damage | Disease Models, Animal | Embryo, Nonmammalian | Erythropoiesis | Gene Expression Profiling | Gene Expression Regulation, Developmental | Gene Knockdown Techniques | Genes, Lethal | Genes, p53 | Hematopoiesis | Hematopoietic Stem Cells | Morphogenesis | Mutation | Nervous System | Oligonucleotide Array Sequence Analysis | Ribosomal Proteins | Transcription Factors | Tumor Suppressor Protein p53 | Zebrafish | Zebrafish Proteins