Nature Medicine9, 1513 - 1519 (2003)
Published online: 9 November 2003; | doi:10.1038/nm961
Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3
Stephen B Ting1, Tomasz Wilanowski1, Alana Auden1, Mark Hall1, Anne K Voss2, Tim Thomas2, Vishwas Parekh3, John M Cunningham3
& Stephen M Jane1
1
Rotary Bone Marrow Research Laboratories, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, Victoria, Australia 3050.
2
Division of Development & Neurobiology, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, Australia 3050.
3
Division of Experimental Hematology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38101, USA.
Correspondence should be addressed to Stephen M Jane jane@wehi.edu.au
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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