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

Nat Med. 2003 Dec;9(12):1513-9. doi: 10.1038/nm961. Epub 2003 Nov 9.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Drug Resistance
  • Epithelium / pathology
  • Female
  • Folic Acid / pharmacology*
  • Humans
  • Inositol / pharmacology*
  • Mice
  • Mice, Knockout
  • Mice, Neurologic Mutants
  • Neural Tube Defects / etiology*
  • Neural Tube Defects / genetics
  • Neural Tube Defects / pathology
  • Neural Tube Defects / prevention & control*
  • Nuclear Proteins
  • Phenotype
  • Pregnancy
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Transcription Factors / physiology


  • DNA-Binding Proteins
  • ELF1 protein, human
  • Elf1 protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • Inositol
  • Folic Acid