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

Nature Medicine volume 9, pages 15131519 (2003) | Download Citation

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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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Acknowledgements

We thank members of the Jane lab and S. Foote for helpful discussions; J. Salmon, S. Vasudevan and Ozgene Inc. for technical assistance; B. Mesiti for help with figure preparation; and staff from the Walter & Eliza Hall Institute for animal support and statistical analyses. This work was supported by grant PO1 HL53749–03 from the National Institutes of Health. S.M.J. is a Senior Research Fellow of the Australian National Health and Medical Research Council. S.B.T is a scholar of the Cancer Council of Victoria. J.M.C. is supported by Cancer Center Support CORE Grant P30 CA 21765, the American Lebanese Syrian Associated Charities and the Assisi Foundation of Memphis.

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Affiliations

  1. Rotary Bone Marrow Research Laboratories, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, Victoria, Australia 3050.

    • Stephen B Ting
    • , Tomasz Wilanowski
    • , Alana Auden
    • , Mark Hall
    •  & Stephen M Jane
  2. Division of Development & Neurobiology, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, Australia 3050.

    • Anne K Voss
    •  & Tim Thomas
  3. Division of Experimental Hematology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38101, USA.

    • Vishwas Parekh
    •  & John M Cunningham

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The authors declare no competing financial interests.

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Correspondence to Stephen M Jane.

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https://doi.org/10.1038/nm961