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Function in Vertebrate
Limb Skeletogenesis: a Modulator of Chondrogenesis


* Department of Microbiology, 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
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
, RAR
, 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
, RAR
, 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.
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