Alx3-deficient mice exhibit folic acid-resistant craniofacial midline and neural tube closure defects.
Neural tube closure defects are among the most frequent congenital malformations in humans. Supplemental maternal intake of folic acid before and during pregnancy reduces their incidence significantly, but the mechanism underlying this preventive effect is unknown. As a number of genes that cause neural tube closure defects encode transcriptional regulators in mice, one possibility is that folic acid could induce the expression of transcription factors to compensate for the primary genetic defect. We report that folic acid is required in mouse embryos for the specific expression of the homeodomain gene Alx3 in the head mesenchyme, an important tissue for cranial neural tube closure. Alx3-deficient mice exhibit increased failure of cranial neural tube closure and increased cell death in the craniofacial region, two effects that are also observed in wild type embryos developing in the absence of folic acid. Folic acid cannot prevent these defects in Alx3-deficient embryos, indicating that one mechanism of folic acid action is through induced expression of Alx3. Thus, Alx3 emerges as a candidate gene for human neural tube defects and reveals the existence of induced transcription factor gene expression as a previously unknown mechanism by which folic acid prevents neural tube closure defects.
Lakhwani
Sita
S
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Spain.
García-Sanz
Patricia
P
Vallejo
Mario
M
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005838:Genotype; D006397:Hematinics; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009436:Neural Tube Defects / Q000235:genetics* / Q000517:prevention & control; D054261:Neurulation; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D006397:Hematinics; D014157:Transcription Factors; D005492:Folic Acid