THE RETINOID LIGAND 4-OXO-RETINOIC ACID IS A HIGHLY-ACTIVE MODULATOR OF POSITIONAL SPECIFICATION

RETINOIDS (vitamin A and its metabolites) are suspected of regulating diverse aspects of growth, differentiation, and patterning during embr yogenesis1, but many questions remain about the identities and functio ns of the endogenous active retinoids involved. The pleiotropic effect s of retinoids may be explained by the existence of complex signal tra nsduction pathways involving diverse nuclear receptors of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families, and at le ast two types of cellular retinoic acid binding proteins (CRABP-I and -II)2. The different RARs, RXRs, and CRABPs have different expression patterns during vertebrate embryogenesis2,3, suggesting that they each have particular functions. Another level at which fine tuning of reti noid action could occur is the metabolism of vitamin A to active metab olites, which may include all-trans-retinoic acid4-7, all-trans-3,4-di dehydroretinoic acid8, 9-cis-retinoic acid9,10, and 14-hydroxy-4,14-re troretinol11. Formation of the metabolite all-trans-4-oxo-retinoic aci d from retinoic acid was considered to be an inactivation pathway duri ng growth and differentiation12,14. We report here that, in contrast, 4-oxo-retinoic acid is a highly active metabolite which can modulate p ositional specification in early embryos. We also show that this retin oid binds avidly to and activates RARbeta, and that it is available in early embryos. The different activities of 4-oxo-retinoic acid and re tinoic acid in modulating positional specification on the one hand, an d growth and differentiation on the other, interest us in the possibil ity that specific retinoid ligands regulate different physiological pr ocesses in vivo.