Exogenous retinoic acid (RA) has teratogenic effects on vertebrate embryos and alters Hox-C gene expression in vivo

Retinoids have long been recognized as teratogens for vertebrate embryos with effects on a wide variety of structures at a number of stages of development (Hale, 1933; Cohlan, 1953; Shenefelt, 1972). The responding organ or structure typically has a period of sensitivity to exogenous retinoids that corresponds approximately to the time of establishment of the anlage for that organ or structure (Shenefelt, 1972). The morphology of some of the retinoid-induced abnormalities has been interpreted as a transformation of anterior cell fates to more posterior cell fates. The most striking morphological transformations are seen in the chick limb bud where local application of retinoids at the anterior margin of the limb bud results in mirror-image duplications of posterior limb structures (reviewed by Tickle, 1991; Tabin, 1991). Recently, retinoid-induced morphological transformations have been documented for structures other than the limb. The otic vesicle is positioned more anteriorly in embryos treated with retinoic acid (RA) in mouse, Xenopus and zebrafish (Sulik et al., 1988; Ruiz i Altaba and Jessell, 1991b; Holder and Hill, 1991), and the extent of the hindbrain and spinal cord may be increased at the expense of the midbrain and forebrain in Xenopus embryos treated with high doses of RA (Durston et al., 1989). Application of exogenous RA to mouse embryos causes somites to form at levels more anterior than normal (Morriss-Kay et al., 1991) as well as causing alterations in the axial skeleton suggestive of anterior-to-posterior transformations (Kessel and Gruss, 1991). The transformation of cell fates implies that important developmental processes, particularly specification along the anterior-posterior (AP) axis, can be disrupted by exogenous retinoids. It is possible that exogenous RA causes anterior-to-posterior transformations by disrupting an endogenous RA-based signalling system which specifies position along the AP axis of the embryo. Vertebrate embryos, including the chick, the mouse and Xenopus, all contain endogenous RA (Thaller and Eichele, 357 Development 116, 357-368 (1992) Printed in Great Britain © The Company of Biologists Limited 1992