Retinoic Acid Treatment Induces the Ectopic Exporession of Retinoic Acid Receptor β Gene and Excessive Cell Death in the Embryonic Mouse Face

Maternal treatment with 100 mg/kg of retinoic acid (RA) on day 9 of gestation in mice caused craniofacial abnormalities of the mandibulofacial dysostosis type. The abnormal morphology was attributed to the excessive cell death in the dorsal aspects of the maxillary and mandibular prominences of the first pharyngeal arch and in the proximal region of the mandibular prominence. To investigate the expression of the RA receptor (RAR) genes in abnormal face morphogenesis, in situ hybridization was performed. The distribution patterns of RAR α and γ transcripts were not altered in the treated embryos. By contrast, the teratogenic dose of RA increased the level of RAR β transcripts, as early as 3 hr after RA-treatment, in the regions where the RAR β expression is at a low level in normal development. The increase of RAR β transcripts was detected by 12 hr, and declined to the low level within 24 hr after the treatment. The regions where ectopic expression of RAR β gene was observed included the areas where the excessive cell death occurred 9-12 hr after RA-treatment. These results suggest that ectopic induction of RAR β by RA may lead to the excessive cell death, threfore may cause abnormal morphogenesis.