Abstract
BackgroundThe role of p53 in the prevention of development of embryos damaged by genotoxic factors is well recognized. However, whether p53 plays an analogous role in preventing birth defects from genetic mutations remains an unanswered question. Genetic screens for mutations affecting development show that only a fraction of developmentally lethal mutations leads to specific phenotypes while the majority results in similar recurrent phenotypes characterized by neuronal apoptosis and developmental delay. Mutations in cell-essential genes typically fall into this group. The observation that mutations in diverse housekeeping genes lead to a similar phenotype suggests a common mechanism underlying this phenotype. For some mutants, p53 inhibition was shown to attenuate the phenotype.Methodology/Principal FindingsTo find out how common p53 involvement is in this phenotype, we analyzed zebrafish mutants from various categories of cell essential genes. Several thousand zebrafish mutants have been identified; many of them are kept at stock centers and available for the research community. We selected mutants for genes functioning in DNA replication, transcription, telomere maintenance, ribosome biogenesis, splicing, chaperoning, endocytosis, and cellular transport. We found that mutants have similar phenotypes including neural apoptosis, failure to develop structures originated from the neural crest cells, and hematopoietic defects. All mutants share p53 upregulation and similar changes in several p53-dependent and independent molecular pathways.Conclusion/SignificanceOur results suggest that mutations in housekeeping genes often canalize on the p53-mediated phenotype. p53 prevents the development of embryos with defects in such genes. p53-mediated changes in gene expression may also contribute to many human congenital malformations.
Highlights
Some time ago, Hall and Lane suggested that the ability of p53 to prevent teratogenesis was the primary driving force behind the evolution of this protein mainly known as a tumor suppressor [1]
Analysis of genes affected in these mutants showed that they encode proteins involved in ribosome biogenesis (31%), chromatin maintenance, DNA replication and repair (17%), transcription (9%), mRNA processing (14%), protein folding and degradation, and other basic cellular functions
We have recently found that zebrafish mutants for ribosomal proteins (RPs) rps8, rps11, rps18, and rpl11 have upregulation of the p53 network [10,11]
Summary
Hall and Lane suggested that the ability of p53 to prevent teratogenesis was the primary driving force behind the evolution of this protein mainly known as a tumor suppressor [1]. Activation of p53 in response to genotoxic stress promotes the death of damaged embryos, and in this way, decreases the incidence of congenital defects among the survivors. The results of mutagenesis screens suggest that disruption of 1,400 to 2,400 genes could lead to early embryonic death in zebrafish [5]. These developmentessential genes tend to be evolutionarily conserved. The role of p53 in the prevention of development of embryos damaged by genotoxic factors is well recognized. Genetic screens for mutations affecting development show that only a fraction of developmentally lethal mutations leads to specific phenotypes while the majority results in similar recurrent phenotypes characterized by neuronal apoptosis and developmental delay. P53 inhibition was shown to attenuate the phenotype
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