The regulation of retinoic acid receptor expression by retinoids in mouse embryos

Retinoic acid (RA) plays an important role in normal embryogenesis; however, excessive doses are highly teratogenic. At present, the molecular mechanism(s) responsible for these effects of RA are not well understood. Examination of the pattern of expression of retinoid nuclear receptors (RARs and RXRs) demonstrates that RAR beta 2 mRNA levels are elevated to the greatest extent in response to exposure of mouse embryos to teratogenic doses of retinoids. The degree of elevation in RAR beta 2 mRNA correlates with susceptible embryonic tissues, sensitive developmental stages and a large number of retinoids with different effectiveness. Furthermore, the elevations of RAR beta 2 must persist for at least 9 hours following retinoid exposure in order to observe malformations. Thus elevations in RAR beta 2 mRNA levels is an excellent molecular marker to predict teratogenic outcome when embryos are exposed to retinoids. Finally, studies utilizing limb bud mesenchymal cells in micromass culture and antisense oligonucleotides directed to RAR beta 2 mRNA provide evidence that elevation in RAR beta 2 mRNA is an important event leading to RA-induced dysmorphogenesis.