Vitamin A is an indispensable factor for normal growth and development. However, retinoic acid and some of its derivatives are potent teratogens in both experimental animals and man. At present several nuclear retinoic acid receptors (RARs and RXR) have been identified. Each of these RARs belong to the steroid nuclear receptor family and presumably act as transcriptional transactivators. Therefore, RARs have been suggested to act as mediators in the regulation of transcription of specific genes by retinoic acid. It is likely that together retinoic acid and the RARs may alter the expression of specific genes during both normal and teratogenic development. Recent studies in our laboratories have demonstrated that teratogenic doses of retinoic acid causes a rapid induction of beta-RAR mRNA in mouse conceptuses. Studies proposed in this grant application are directed towards the determination of the relationship between teratogenic doses of retinoic acid and the induction of beta-RAR mRNA. Specifically, we plan, (1) to understand the molecular regulation of expression of beta-RAR in mouse conceptuses treated with teratogenic doses of retinoic acid; (2) to determine the developmental effects of elevated levels of beta-RAR mRNA in mouse conceptuses treated with normal and teratogenic doses of retinoic acid; and (3) to determine the developmental effects of inactivation of the beta-RAR gene(s) in mouse conceptuses treated with normal and teratogenic doses of retinoic acid. These studies will lead to the identification and better characterization of the role of beta-RAR in both normal and abnormal (teratogenic) development.
