Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3

Stephen Bek Ngie Ting, Tomasz Wilanowski, Alana Auden, Mark A Hall, Anne K Voss, Tim Thomas, Vishwas Parekh, John M Cunningham, Stephen Marsden Jane

Research output: Contribution to journalArticleResearchpeer-review

140 Citations (Scopus)

Abstract

The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene, grainyhead-like-3 (Grhl3), is a compelling candidate for the gene underlying the curly tail phenotype. The NTDs in Grhl3-null mice are more severe than those in the curly tail strain, as the Grhl3 alleles in ct/ct mice are hypomorphic. Spina bifida in ct/ct mice is folate resistant, but its incidence can be markedly reduced by maternal inositol supplementation periconceptually. The NTDs in Grhl3 -/- embryos are also folate resistant, but unlike those in ct/ct mice, they are resistant to inositol. These findings suggest that residual Grhl3 expression in ct/ct mice may be required for inositol rescue of folate-resistant NTDs.
Original languageEnglish
Pages (from-to)1513 - 1519
Number of pages7
JournalNature Medicine
Volume9
Issue number12
DOIs
Publication statusPublished - 2003

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