Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3.
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.
Ting
Stephen B
SB
Rotary Bone Marrow Research Laboratories, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, Victoria, Australia 3050.
Wilanowski
Tomasz
T
Auden
Alana
A
Hall
Mark
M
Voss
Anne K
AK
Thomas
Tim
T
Parekh
Vishwas
V
Cunningham
John M
JM
Jane
Stephen M
SM
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004351:Drug Resistance; D004848:Epithelium / Q000473:pathology; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D006801:Humans; D007294:Inositol / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009436:Neural Tube Defects / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009687:Nuclear Proteins; D010641:Phenotype; D011247:Pregnancy; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; C512897:ELF1 protein, human; C512896:Elf1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D007294:Inositol; D005492:Folic Acid