Neural tube defects: prevention by folic acid and other vitamins.
ABSTRACT Folic acid has been demonstrated in clinical trials to reduce significantly the recurrence (and probably occurrence) of neural tube defects (NTD). In the U.K., there has been no decline in prevalence of NTD since the publication of the findings with folic acid. This article examines a series of questions relating to the action of folic acid, with emphasis on the use of mouse models as a source of experimental information which cannot easily be obtained by direct study of humans. Several mouse genetic NTD models exhibit sensitivity to prevention by folic acid, whereas other mice which develop morphologically similar NTD are resistant. Folic acid normalises neurulation in the sensitive mouse strains, providing evidence for a direct effect on the developing embryo, not on the pregnant female: Mouse studies do not support the proposed action of folic acid in encouraging the in utero demise of affected fetuses (i.e. terathanasia). Polymorphic variants of several folate-related enzymes have been shown to influence risk of NTD in humans and an inherited abnormality of folate metabolism has been demonstrated in one mouse NTD model. However, the biochemical basis of the action of folic acid in preventing NTD remains to be determined in detail. NTD in one folate-resistant mouse strain can be prevented by myo-inositol, both in utero and in vitro, raising the possibility of a therapeutic role also in humans. Gene-gene interactions seem likely to underlie the majority of NTD, suggesting that poly-therapy involving folic acid and other agents, such as myo-inositol, may prove more effective in preventing NTD than folic acid treatment alone.
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Article: Neural tube defects: prevention by folic acid and other vitamins.
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ABSTRACT: Cited2 (also Mrg1/p35srj) is a member of a new conserved gene family that is expressed during mouse development and in adult tissues. In order to investigate the function of Cited2 during mouse embryogenesis, we introduced a null mutation into the Cited2 locus. Cited2(-/-) mutants died at late gestation and exhibited heart defects and exencephaly, arising from defective closure of the midbrain (MB) and hindbrain. Initiation of neural tube closure at the forebrain-midbrain (FB-MB) boundary, an essential step for closure of the cranial neural tube, was impaired in the Cited2(-/-) mutants. Gene marker analysis using in situ hybridization revealed that the patterning of the anterior neural plate and head mesenchyme was little affected or normal in the Cited2(-/-) embryos. However, Cited2 was required for the survival of neuroepithelial cells and its absence led to massive apoptosis in dorsal neuroectoderm around the FB-MB boundary and in a restricted transverse domain in the hindbrain. Treatment with folic acid significantly reduced the exencephalic phenotype in the Cited2(-/-) embryos both in vivo and in vitro. However, assessment of folate metabolism revealed no defect in the Cited2(-/-) mutants, and the elevated apoptosis observed in the neuroepithelium of the Cited2(-/-) mutants was apparently not decreased by folic acid supplementation. To our knowledge, the Cited2 mouse represents the first genetic model in which folic acid can prevent a defect in neural tube closure by a mechanism other than the neutralization of a defect in folate homeostasis.Human Molecular Genetics 03/2002; 11(3):283-93. · 6.68 Impact Factor
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ABSTRACT: Arylamine N-acetyltransferases (NATs) are polymorphic xenobiotic metabolising enzymes, linked to cancer susceptibility in a variety of tissues. In humans and in mice there are multiple NAT isoforms. To identify whether the different isoforms represent inbuilt redundancy or whether they have unique roles, we have generated mice with a null allele of Nat2 by gene targeting. This mouse line conclusively demonstrates that the different isoforms have distinct functions with no compensatory expression in the Nat2 null animals of the other isoforms. In addition, we have used the transgenic line to show the pattern of Nat2 expression during development. Although Nat2 is not essential for embryonic development, it has a widespread tissue distribution from at least embryonic day 9.5. This mouse line now paves the way for the teratological role of Nat2 to be tested.The Pharmacogenomics Journal 02/2003; 3(3):169-77. DOI:10.1038/sj.tpj.6500170 · 5.51 Impact Factor
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ABSTRACT: A proportion of neural tube defects (NTDs) can be prevented by maternal folic acid supplementation, although some cases are unresponsive. The curly tail mutant mouse provides a model of folate-resistant NTDs, in which defects can be prevented by inositol therapy in early pregnancy. Hence, inositol represents a possible novel adjunct therapy to prevent human NTDs. The present study investigated the molecular mechanism by which inositol prevents mouse NTDs. Activation of protein kinase C (PKC) is known to be essential, and we examined neurulation-stage embryos for PKC expression and applied PKC inhibitors to curly tail embryos developing in culture. Although all known PKC isoforms were detected in the closing neural tube, use of chemical PKC inhibitors identified a particular requirement for 'conventional' PKC isoforms. Peptide inhibitors offer selective inhibition of individual PKCs, and we demonstrated isoform-specific inhibition of PKC in embryonic cell cultures. Application of peptide inhibitors to neurulation-stage embryos revealed an absolute dependence on the activity of PKCbetaI and gamma for prevention of NTDs by inositol, and partial dependence on PKCzeta, whereas other PKCs (alpha, betaII delta, and epsilon) were dispensable. To investigate the cellular action of inositol and PKCs in NTD prevention, we examined cell proliferation in curly tail embryos. Defective proliferation of hindgut cells is a key component of the pathogenic sequence leading to NTDs in curly tail. Hindgut cell proliferation was stimulated specifically by inositol, an effect that required activation of PKCbetaI. Our findings reveal an essential role of specific PKC isoforms in mediating the prevention of mouse NTDs by inositol.Human Molecular Genetics 02/2004; 13(1):7-14. DOI:10.1093/hmg/ddh003 · 6.68 Impact Factor