FUNCTION OF THE RETINOIC ACID RECEPTORS (RARS) DURING DEVELOPMENT .1.CRANIOFACIAL AND SKELETAL ABNORMALITIES IN RAR DOUBLE MUTANTS

Numerous congenital malformations have been observed in fetuses of vit amin A-deficient (VAD) dams [Wilson, J. G., Roth, C. B., Warkany, J., (1953), Am. J. Anat. 92, 189-217]. Previous studies of retinoic acid r eceptor (RAR) mutant mice have not revealed any of these malformations [Li, E., Sucov, H. M., Lee, K.-F., Evans, R. M., Jaenisch, R. (1993) Proc. Natl. Acad. Sci. USA 90, 1590-1594; Lohnes, D., Kastner, P., Die rich, A., Mark, M., LeMeur, M., Chambon, P. (1993) Cell 73, 643-658; L ufkin, T., Lohnes, D., Mark, M., Dierich, A., Gorry, P., Gaub, M. P., LeMeur, M., Chambon, P. (1993) Proc. Natl. Acad. Sci. USA 90, 7225-722 9; Mendelsohn, C., Mark, M., Dolle, P., Dierich, A., Gaub, M.P., Krust , A., Lampron, C., Chambon, P. (1994a) Dev. Biol. in press], suggestin g either that there is a considerable functional redundancy among memb ers of the RAR family during ontogenesis or that the RARs are not esse ntial transducers of the retinoid signal in vivo. In order to discrimi nate between these possibilities, we have generated a series of RAR co mpound null mutants. These RAR double mutants invariably died either i n utero or shortly after birth and presented a number of congenital ab normalities, which are reported in this and in the accompanying study. We describe here multiple eye abnormalities which are found in variou s RAR double mutant fetuses and are similar to those previously seen i n VAD fetuses. Interestingly, we found further abnormalities not previ ously reported in VAD fetuses. These abnormalities affect ocular gland s, salivary glands and their associated ducts, the axial and limb skel eton, and all skeletal elements derived from the mesectoderm of the fr ontonasal mass and of the second and third pharyngeal arches. RAR doub le mutants also exhibit supernumerary cranial skeletal elements that a re present in the ancestral reptilian skull. The role of retinoic acid (RA) and of the RARs in the ontogenesis of the affected structures, p articularly of those that are derived from mesenchymal neural crest ce lls, is discussed.