Screening for novel <i>PAX3</i> polymorphisms and risks of spina bifida

Lü, Wei; Zhu, Huiping; Wen, Shu; Laurent, Cecile A.; Shaw, Gary M.; Lammer, Edward J.; Finnell, Richard H.

doi:10.1002/bdra.20322

Cited by 23 publications

(19 citation statements)

References 15 publications

(13 reference statements)

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“…Pax3 is expressed in the dorsal neuroepithelial cells along the entire anterior-posterior axis during the closure process (Goulding et al, 1991;Solloway and Robertson, 1999). A recent study suggests the association of PAX3 mutations with spina bifida in humans (Agopian et al, 2013), which was not found in early studies Lu et al, 2007). Pax3 homozygous mutant mouse embryos exhibit both spina bifida and exencephaly Epstein et al, 1991), whereas the latter is not seen in the β-catenin cKO mutant.…”

Section: Pax3 Mediates β-Catenin Signaling For Caudal Neural Tube Clomentioning

confidence: 85%

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

et al. 2014

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Non-canonical Wnt/planar cell polarity (PCP) signaling plays a primary role in the convergent extension that drives neural tube closure and body axis elongation. PCP signaling gene mutations cause severe neural tube defects (NTDs). However, the role of canonical Wnt/β-catenin signaling in neural tube closure and NTDs remains poorly understood. This study shows that conditional gene targeting of β-catenin in the dorsal neural folds of mouse embryos represses the expression of the homeobox-containing genes Pax3 and Cdx2 at the dorsal posterior neuropore (PNP), and subsequently diminishes the expression of the Wnt/β-catenin signaling target genes T, Tbx6 and Fgf8 at the tail bud, leading to spina bifida aperta, caudal axis bending and tail truncation. We demonstrate that Pax3 and Cdx2 are novel downstream targets of Wnt/β-catenin signaling. Transgenic activation of Pax3 cDNA can rescue the closure defect in the β-catenin mutants, suggesting that Pax3 is a key downstream effector of β-catenin signaling in the PNP closure process. Cdx2 is known to be crucial in posterior axis elongation and in neural tube closure. We found that Cdx2 expression is also repressed in the dorsal PNPs of Pax3-null embryos. However, the ectopically activated Pax3 in the β-catenin mutants cannot restore Cdx2 mRNA in the dorsal PNP, suggesting that the presence of both β-catenin and Pax3 is required for regional Cdx2 expression. Thus, β-catenin signaling is required for caudal neural tube closure and elongation, acting through the transcriptional regulation of key target genes in the PNP.

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Section: Pax3 Mediates β-Catenin Signaling For Caudal Neural Tube Clomentioning

confidence: 85%

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

et al. 2014

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“…However, screening of NTD populations for mutations in PAX3 or for association with particular SNP haplotypes does not suggest that PAX3 is a major genetic component of human NTDs (Trembath et al, 1999;Lu et al, 2007). Although mutation of PAX3 seems capable of causing NTDs in humans as in mice, the relative contribution of such mutations to the overall burden of NTDs remains unclear.…”

Section: Pax3 and Human Neural Tube Defectsmentioning

confidence: 94%

Understanding the causes and prevention of neural tube defects: Insights from the splotch mouse model

Greene¹,

Massa²,

Copp³

2009

Birth Defects Research

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Splotch mutant mice develop neural tube defects (NTDs), comprising exencephaly and/or spina bifida, as well as neural crest-related defects and abnormalities of limb musculature. Defects in splotch mice result from mutations in Pax3, and some human NTDs may also result from mutations in the human PAX3 gene. Pax3 encodes a transcription factor whose function may influence expression of multiple downstream genes associated with a variety of cellular properties (including apoptosis, adhesion, proliferation, and differentiation), that could be important for neural tube closure. The frequency of NTDs varies between mutant alleles and is also influenced by genetic background and environmental factors. Notably, splotch provides a model for folic acid-preventable NTDs, and conversely, dietary folate deficiency exacerbates NTDs. Understanding the molecular and cellular basis of splotch NTDs, as well as the mechanisms by which the frequency of defects is influenced by genetic and environmental factors (such as sub-optimal folate status), may provide insight into the causation of these severe congenital malformations in humans.

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“…NTDs in the Splotch mutant can be rescued with supplemental dietary folic acid or thymidine, indicating that folic acid prevents NTDs by rescuing de novo thymidylate synthesis in this mouse model (9,10). However, Pax3 has not been linked to human NTD pathogenesis in epidemiologic studies (13,14).…”

Section: Introductionmentioning

confidence: 99%

Shmt1 and de novo thymidylate biosynthesis underlie folate-responsive neural tube defects in mice

Beaudin¹,

Abarinov²,

Noden³

et al. 2011

The American Journal of Clinical Nutrition

106

108

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Background: Folic acid supplementation prevents the occurrence and recurrence of neural tube defects (NTDs), but the causal metabolic pathways underlying folic acid-responsive NTDs have not been established. Serine hydroxymethyltransferase (SHMT1) partitions folate-derived one-carbon units to thymidylate biosynthesis at the expense of cellular methylation, and therefore SHMT1-deficient mice are a model to investigate the metabolic origin of folate-associated pathologies. Objectives: We examined whether genetic disruption of the Shmt1 gene in mice induces NTDs in response to maternal folate and choline deficiency and whether a corresponding disruption in de novo thymidylate biosynthesis underlies NTD pathogenesis. Design: Shmt1 wild-type, Shmt1 +/2 , and Shmt1 2/2 mice fed either folate-and choline-sufficient or folate-and choline-deficient diets were bred, and litters were examined for the presence of NTDs. Biomarkers of impaired folate metabolism were measured in the dams. In addition, the effect of Shmt1 disruption on NTD incidence was investigated in Pax3 Sp mice, an established folate-responsive NTD mouse model. Results: Shmt1 +/2 and Shmt1 2/2 embryos exhibited exencephaly in response to maternal folate and choline deficiency. Shmt1 disruption on the Pax3 Sp background exacerbated NTD frequency and severity. Pax3 disruption impaired de novo thymidylate and purine biosynthesis and altered amounts of SHMT1 and thymidylate synthase protein.Conclusions: SHMT1 is the only folate-metabolizing enzyme that has been shown to affect neural tube closure in mice by directly inhibiting folate metabolism. These results provide evidence that disruption of Shmt1 expression causes NTDs by impairing thymidylate biosynthesis and shows that changes in the expression of genes that encode folate-dependent enzymes may be key determinates of NTD risk.Am J Clin Nutr 2011;93:789-98.

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Screening for novel PAX3 polymorphisms and risks of spina bifida

Cited by 23 publications

References 15 publications

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation

Understanding the causes and prevention of neural tube defects: Insights from the splotch mouse model

Shmt1 and de novo thymidylate biosynthesis underlie folate-responsive neural tube defects in mice

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