Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3- dependent development and tumorigenesis

Pani, Lydie; Horal, Melissa; Loeken, Mary R.

doi:10.1101/gad.969302

Cited by 186 publications

(181 citation statements)

References 33 publications

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“…This is consistent with the fact that Tead2 is expressed exclusively in mitotic neuroepithelial cells during fetal brain development (Jacquemin et al, 1996;Yasunami et al, 1995). Moreover, as previously reported for Pax3 mutants (Pani et al, 2002), injection of pregnant females with pifithrin-α, an inhibitor of p53 signaling (Murphy et al, 2004), suppressed exencephaly in Tead2 nullizygous females (Table 3B), suggesting that inhibition of apoptosis can rescue this NTD. However, the NTD seen in Tead2 nullizygous mice contrasts with that observed in Pax3 nullizygous mice.…”

Section: Discussionsupporting

confidence: 90%

“…Pifithrin-α, an inhibitor of p53-dependent apoptosis (Murphy et al, 2004), has been reported to rescue NTDs in Pax3-deficient embryos (Pani et al, 2002). Similarly, pifithrin-α also prevented Tead2-dependent exencephaly to the same extent as did folic acid (Table 3B), suggesting that TEAD2 may regulate neural tube closure by inhibiting p53-dependent apoptosis, rather than by inducing neural tube-specific gene expression.…”

Section: Tead2 Is Involved In Neural Tube Closurementioning

confidence: 86%

“…Results from three litters were combined. (B) At E8.5 and E9.5, pregnant females were injected intraperitoneally with pifithrin-α (Pani et al, 2002), and the embryos were examined at E13.5 for NTDs and genotyped. Results from three litters were combined.…”

Section: Figmentioning

confidence: 99%

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Transcription factor TEAD2 is involved in neural tube closure

Kaneko

Kohn

Liu

et al. 2007

Genesis

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Summary-TEAD2, one of the first transcription factors expressed at the beginning of mammalian development, appears to be required during neural development. For example, Tead2 expression is greatest in the dorsal neural crest where it appears to regulate expression of Pax3, a gene essential for brain development. Consistent with this hypothesis, we found that inactivation of the Tead2 gene in mice significantly increased the risk of exencephaly (a defect in neural tube closure). However, none of the embryos exhibited spina bifida, the major phenotype of Pax3 nullizygous embryos, and expression of Pax3 in E11.5 Tead2 nullizygous embryos was normal. Thus, Tead2 plays a role in neural tube closure that is independent of its putative role in Pax3 regulation. In addition, the risk of exencephaly was greatest with Tead2 nullizygous females, and could be suppressed either by folic acid or pifithrin-α. These results reveal a maternal genetic contribution to neural tube closure, and suggest that Tead2-deficient mice provide a model for anencephaly, a common human birth defect that can be prevented by folic acid. genesis 45:577-587, 2007.

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Section: Discussionsupporting

confidence: 90%

Section: Tead2 Is Involved In Neural Tube Closurementioning

confidence: 86%

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Transcription factor TEAD2 is involved in neural tube closure

Kaneko

Kohn

Liu

et al. 2007

Genesis

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“…We recently showed that Pax-3 down regulates p53 protein, and that NTD can be prevented in Pax-3-deficient Sp/Sp embryos by p53 deficiency [49]. Thus, apoptosis is ultimately responsible for the NTD associated with Pax-3 deficiency, but only because Pax-3 is needed to inhibit p53-dependent apoptosis until fusion of the neural tube is complete.…”

Section: Discussionmentioning

confidence: 99%

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

et al. 2003

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Aims/hypothesis. Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. Methods. Maternal diabetes-induced oxidative stress was blocked with α-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis.Results. Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and α-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by α-tocopherol and GSHethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. Conclusion/interpretation. Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress. [Diabetologia (2003) 46:538-545]

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“…The paired-box domain is a highly conserved DNA-binding domain of 128 amino acids located at the amino terminus of the protein. Analysis of mouse models and human syndromes has revealed the importance of PAX genes in their role as regulators of normal development (Mansouri et al, 1999;Pani et al, 2002). Heterozygous splotch mice display pigmentary abnormalities while homozygotes die during gestation with spina bifida or exencephaly (Vogan et al, 1993;Auerbach, 1954).…”

Section: Introductionmentioning

confidence: 99%

Screening for novel PAX3 polymorphisms and risks of spina bifida

Lü

Zhu

Wen

et al. 2006

Birth Defects Research

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BACKGROUND: PAX3 plays an important role in mammalian embryonic development. Known mutations in PAX3 are etiologically associated with Waardenburg syndrome and syndromic neural tube defects (NTDs). Mutations in the murine homologue, pax3, are responsible for the phenotype of splotch mice, in which nullizygotes are 100% penetrant for NTDs. METHODS: The study sample included 74 infants with spina bifida (cases) and 87 nonmalformed infant controls. The conserved paired-box domain as well as the upstream genomic region of PAX3 were subjected to resequencing and those identified SNPs were evaluated as haplotypes. The associations of haplotypes for selected gene regions and the risks of spina bifida were further studied. RESULTS: Nineteen SNPs were observed; 15 observed in controls had been submitted to the National Center for Biotechnology Information (NCBI) database with allele frequencies. The PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC of nine SNPs, were found to be associated with an increased risk of spina bifida, with an OR of 3.5 (95% CI: 1.2-10.0) among Hispanic Whites. CONCLUSIONS: Our analyses indicated that PAX3 SNPs were not strong risk factors for human spina bifida. However, additional follow-up of the PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC, may be important in other populations.

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Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3- dependent development and tumorigenesis

Cited by 186 publications

References 33 publications

Transcription factor TEAD2 is involved in neural tube closure

Transcription factor TEAD2 is involved in neural tube closure

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

Screening for novel PAX3 polymorphisms and risks of spina bifida

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