Publication in detail

Nat Med 2003 Dec;9(12):1513-9. Epub 2003 No

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

Auden, A; Cunningham, JM; Hall, M; Jane, SM.; Parekh, V; Thomas, T; Ting, SB; Voss, AK; Wilanowski, T

Royal Melbourne Hospital Post Office, Grattan Street, Parkville, Victoria, Australia 3050.

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.

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