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© The Rockefeller University Press,
0021-9525/1997//445 $5.00
The Journal of Cell Biology, Volume 136, Number 2,
, 1997 445-457
Article |
Retinoic Acid Receptor 
Function in Vertebrate Limb Skeletogenesis: a Modulator of Chondrogenesis
Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710; Institut für Saeugetiergenetik, GSF-Forschungsinstitut Neuherberg, D-85764 Oberschleissheim, Germany; and || 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, RAR
, RARβ, and RAR
, 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 RAR, RARβ, and RAR 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 RAR 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 RAR revealed that downregulation of RAR is important in allowing the chondrogenic phenotype to be expressed. These results demonstrate a specific function for RAR in limb development and the regulation of chondroblast differentiation.
Abbreviations used in this paper: E, embryonic day; RA, retinoic acid; RAR, RA receptor; RXR, retinoid X receptor; tgRAR, transgenic RAR.
D. Cash has been supported by Public Health Service (PHS) predoctoral training grant CA09111. This research was supported by a PHS grant CA39066 to E. Linney and a Medical Research Council of Canada grant MT-13676 to T.M. Underhill. The transgenic mice were produced by the shared transgenic mouse resource of the Duke University Comprehensive Cancer Center. All experiments conducted with animals were performed in accordance with the Duke University Institutional Animal Care & Use Committee Protocol.
Address all correspondence to T. Michael Underhill, Skeletal Biology Group, Division of Oral Biology, Faculty of Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1. Tel.: (519) 6613327, ext. 6111. Fax: (519) 661-3875. E-mail: tunderhi{at}julian.uwo.ca
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