Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3
Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3
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DOI：
10.1038/nm961
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发表时间：
2003-12-01
期刊：
影响因子：
82.9
通讯作者：
Jane, SM
中科院分区：
文献类型：
--
作者：
Ting, SB;Wilanowski, T;Jane, SM
神经管缺陷、脊柱裂和无脑畸形是广泛存在的严重出生缺陷。小鼠突变卷曲尾（ct/ ct）已经作为NTD的模型50年了，尽管负责的遗传缺陷仍然没有被认识到。在这里，我们通过基因靶向、定位和遗传互补研究表明，果蝇grainyhead（grh）基因的小鼠同源物grainyhead- like- 3（Grhl 3）是卷曲尾表型基因的一个令人信服的候选者。Grhl 3缺失小鼠中的NTD比卷尾品系中的NTD更严重，因为ct/ ct小鼠中的Grhl 3等位基因是亚型的。ct/ ct小鼠的脊柱裂对叶酸有抵抗力，但母体补充肌醇可显著降低其发病率。Grhl 3（-/-）胚胎中的NTD也具有叶酸抗性，但与ct/ ct小鼠中的NTD不同，它们对肌醇具有抗性。这些发现表明ct/ ct小鼠中的残留Grhl 3表达可能是叶酸抗性NTD的肌醇拯救所需的。
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.