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J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/01/445/13 $2.00
Volume 136, Number 2, January 27, 1997 445-457

Retinoic Acid Receptor alpha  Function in Vertebrate Limb Skeletogenesis: a Modulator of Chondrogenesis

David E. Cash,* Cheryl B. Bock,Dagger Klaus Schughart,§ Elwood Linney,* and T. Michael Underhillpar

* Department of Microbiology, Dagger  Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710; § Institut für Saeugetiergenetik, GSF-Forschungsinstitut Neuherberg, D-85764 Oberschleissheim, Germany; and par  Division of Oral Biology, Faculty of Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1

Retinoic acid is a signaling molecule involved in the regulation of growth and morphogenesis during development. There are three types of nuclear receptors for all-trans retinoic acid in mammals, RARalpha , RARbeta , and RARgamma , which transduce the retinoic acid signal by inducing or repressing the transcription of target genes (Leid, M., P. Kastner, and P. Chambon. 1992. Trends Biochem. Sci. 17:427-433). While RARalpha , RARbeta , and RARgamma are expressed in distinct but overlapping patterns in the developing mouse limb, their exact role in limb development remains unclear. To better understand the role of retinoic acid receptors in mammalian limb development, we have ectopically expressed a modified RARalpha with constitutive activity (Balkan, W., G.K. Klintworth, C.B. Bock, and E. Linney. 1992. Dev. Biol. 151:622-625) in the limbs of transgenic mice. Overexpression of the transgene was associated with marked pre- and postaxial limb defects, particularly in the hind limb, where expression of the transgene was consistently seen across the whole anteroposterior axis. The defects displayed in these mice recapitulate, to a large degree, many of the congenital limb malformations observed in the fetuses of dams administered high doses of retinoic acid (Kochhar, D.M. 1973. Teratology. 7:289-295). Further analysis of these transgenic animals showed that the defect in skeletogenesis resided at the level of chondrogenesis. Comparison of the expression of the transgene relative to that of endogenous RARalpha revealed that downregulation of RARalpha is important in allowing the chondrogenic phenotype to be expressed. These results demonstrate a specific function for RARalpha in limb development and the regulation of chondroblast differentiation.


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