RETINOIC-ACID-RECEPTOR-ALPHA FUNCTION IN VERTEBRATE LIMB SKELETOGENESIS - A MODULATOR OF CHONDROGENESIS

Retinoic acid is a signaling molecule involved in the regulation of gr owth and morphogenesis during development. There are three types of nu clear receptors for all-trans retinoic acid in mammals, RAR alpha, RAR beta, and RAR gamma, which transduce the retinoic acid signal by indu cing or repressing the transcription of target genes (Leid, M., P, Kas tner, and P. Chambon, 1992. Trends Biochem. Sci. 17:427-433). While RA R alpha, RAR beta, and RAR gamma are expressed in distinct but overlap ping patterns in the developing mouse limb, their exact role in limb d evelopment remains unclear, To better understand the role of retinoic acid receptors in mammalian limb development, we have ectopically expr essed a modified RAR alpha with constitutive activity (Balkan, W., G.K . Klintworth, C.B. Beck, and E. Linney, 1992. Dev. Biol. 151:622-625) in the limbs of transgenic mice. Overexpression of the transgene was a ssociated with marked pre- and postaxial limb defects, particularly in the hind limb, where expression of the transgene was consistently see n across the whole anteroposterior axis, The defects displayed in thes e mice recapitulate, to a large degree, many of the congenital limb ma lformations observed in the fetuses of dams administered high doses of retinoic acid (Kochhar, D.M. 1973. Teratology. 7:289-295). Further an alysis of these transgenic animals showed that the defect in skeletoge nesis resided at the level of chondrogenesis, Comparison of the expres sion of the transgene relative to that of endogenous RAR alpha reveale d that downregulation of RAR alpha is important in allowing the chondr ogenic phenotype to be expressed. These results demonstrate a specific function for RAR alpha in limb development and the regulation of chon droblast differentiation.