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doi: 10.1242/10.1242/dev.00428
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France
* Author for correspondence (e-mail: marek{at}igbmc.u-strasbg.fr)
Accepted 5 February 2003
Fusion and hypoplasia of the first two branchial arches, a defect typically
observed in retinoic acid (RA) embryopathy, is generated in cultured mouse
embryos upon treatment with BMS453, a synthetic compound that exhibits
retinoic acid receptor ß (RARß) agonistic properties in transfected
cells. By contrast, no branchial arch defects are observed following treatment
with synthetic retinoids that exhibit RAR
or RAR
agonistic
properties. The BMS453-induced branchial arch defects are mediated through RAR
activation, as they are similar to those generated by a selective pan-RAR
agonist, are prevented by a selective pan-RAR antagonist and cannot be
mimicked by exposure to a pan-RXR agonist alone. They are enhanced in the
presence of a pan-RXR agonist, and cannot be generated in Rarb-null
embryos. Furthermore, they are accompanied, in the morphologically altered
region, by ectopic expression of Rarb and of several other direct RA
target genes. Therefore, craniofacial abnormalities characteristic of the RA
embryopathy are mediated through ectopic activation of RARß/RXR
heterodimers, in which the ligand-dependent activity of RXR is subordinated to
that of RARß. Endodermal cells lining the first two branchial arches
respond to treatment with the RARß agonist, in contrast to neural crest
cells and ectoderm, which suggests that a faulty endodermal regionalization is
directly responsible for RA-induced branchial arch dysmorphologies.
Additionally, we provide the first in vivo evidence that the synthetic
RARß agonist BMS453 exhibits an antagonistic activity on the two other
RAR isotypes.
Key words: Retinoic acid embryopathy, Synthetic retinoids, Nuclear receptors, Embryo cultures, Endoderm, Branchial arches, Pharyngeal pouches, Mouse, Synergy, Agonists, Antagonists, Teratogenicity
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