Role of p53 family in birth defects: Lessons from zebrafish

Danilova, Nadia; Sakamoto, Kathleen M.; Lin, Shuo

doi:10.1002/bdrc.20129

Cited by 10 publications

(6 citation statements)

References 154 publications

(176 reference statements)

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“…Upregulation of p53 was also noted in a mutant for recycling factor p110 [14]. Notably that the phenotype characterized by excessive neuronal apoptosis can be induced in zebrafish by activating p53 through various treatments [15], [16]. Altogether, these data suggest that p53 may mediate non-specific phenotype of mutants for housekeeping genes.…”

Section: Resultsmentioning

confidence: 78%

p53 Upregulation Is a Frequent Response to Deficiency of Cell-Essential Genes

2010

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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.

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Section: Resultsmentioning

confidence: 78%

p53 Upregulation Is a Frequent Response to Deficiency of Cell-Essential Genes

2010

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“…In response to DNA damage such as UV irradiation or CPT treatment, the increased expression of p53 could increase the binding ability of p53 with its cognate mRNA. p53 protein family is an important teratologic suppressor, but in certain conditions it can cause congenital abnormalities [16]. Maintaining appropriate level of p53 protein is pivotal for zebrafish normal development.…”

Section: Discussionmentioning

confidence: 99%

“…p53 protein family is an important teratologic suppressor, but in certain conditions it can cause congenital abnormalities [16]. Maintaining appropriate level of p53 protein is pivotal for zebrafish normal development.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that p53 plays pivotal roles in the development of zebrafish embryos [16]. Maintaining the appropriate level of p53 protein is important for zebrafish development.…”

Section: Introductionmentioning

confidence: 99%

“…The zebrafish, Danio rerio, is an ideal model organism for studying developmental biology due to its unique characteristics, including high fecundity, short reproductive cycle, external fertilization, and transparency that permits visual assessment of developing cells and organs [11][12][13][14][15]. Studies have shown that p53 plays pivotal roles in the development of zebrafish embryos [16]. Maintaining the appropriate level of p53 protein is important for zebrafish development.…”

Section: Introductionmentioning

confidence: 99%

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Zebrafish p53 protein enhances the translation of its own mRNA in response to UV irradiation and CPT treatment

Zhao

Ding

et al. 2012

FEBS Letters

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Edited by Varda RotterKeywords: p53 Zebrafish RNA binding protein Translational regulation a b s t r a c t p53 protein is an important regulatory factor involved in cell growth and development. In our previous study, we demonstrated that recombined zebrafish p53 protein could specifically bind to its own mRNA in vitro. To determine if a similar interaction exists in zebrafish and if this interaction affects zebrafish development, in the present study, we investigated the interaction of p53 protein and its mRNA in zebrafish embryos. Our results revealed that expressed zebrafish p53 protein could bind with its own mRNA in zebrafish embryos. Furthermore, the endogenous activated or ectopically expressed p53 protein could enhance the relative activity of Renilla luciferase fused with p53 3 0 UTR in response to UV irradiation and CPT treatment, and retarded development of zebrafish embryos was observed.

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Synergistic regulation of p53 by Mdm2 and Mdm4 is critical in cardiac endocardial cushion morphogenesis during heart development

Qin

Chen

et al. 2012

The Journal of Pathology

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Congenital heart defects (CHDs) are the most prevalent human birth defects. More than 85% of CHDs are thought to result from a combination of genetic susceptibilities and environmental stress. However, the stress-related signalling pathways involved remain largely unknown. The p53 transcription factor is a key tumour suppressor and a central regulator of the cellular stress responses. p53 activities are tightly regulated by its inhibitors Mdm2 and Mdm4 at the post-translational level. Here we used the Cre-loxP system to delete Mdm2 (Tie2Cre;Mdm2(FM/FM) ) or one copy of both Mdm2 and Mdm4 (Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) ) in endothelial/endocardial cells and their derivatives in mice to examine the regulation of the p53/Mdm2-Mdm4 pathway during vascular and cardiovascular development. The Tie2Cre;Mdm2(FM/FM) mice died before embryonic day 10.5 (E10.5) and displayed severe vascular defects. On the other hand, the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) mice displayed atrial and ventricular septal defects (ASD, VSD) of the heart, leading to severe heart dysfunction and postnatal death. During cardiac endocardial cushion morphogenesis, p53 activation was associated with defects in both the epithelial-mesenchymal transition (EMT) of the endocardial cells and the post-EMT proliferation of the mesenchymal cells, and the valvuloseptal phenotypes of the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) mice were fully rescued by deletion of one copy of p53. Strikingly, maternal exposure to low-dose X-rays in C57BL/6 mice mimicked the congenital heart malformations seen in the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) model, which was also dependent on p53 status, establishing a link between maternal exposures and CHD susceptibility through the p53 pathway. These data revealed a new regulatory mechanism in cardiac endocardial cushion morphogenesis and suggested a possible cause of CHDs due to environmental stress.

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Role of p53 family in birth defects: Lessons from zebrafish

Cited by 10 publications

References 154 publications

p53 Upregulation Is a Frequent Response to Deficiency of Cell-Essential Genes

p53 Upregulation Is a Frequent Response to Deficiency of Cell-Essential Genes

Zebrafish p53 protein enhances the translation of its own mRNA in response to UV irradiation and CPT treatment

Synergistic regulation of p53 by Mdm2 and Mdm4 is critical in cardiac endocardial cushion morphogenesis during heart development

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